Bibliography, page 6

1. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 31592194
   KDM3B suppresses APL progression by restricting chromatin accessibility and facilitating the ATRA-mediated degradation of PML/RARalpha.

   Wang X; Fan H; Xu C; Jiang G; Wang H; Zhang J · Cancer Cell Int 2019
   used by KDM3B - the H3K9me1/2 demethylase that sits on the KMT2A breakpoint cluster region and keeps it from rearranging, and the only leukaemia gene in this graph whose direction of effect flips between the myeloid and the lymphoid literature
2. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31434704
   The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

   Agger K, Nishimura K, Miyagi S, Messling JE, Rasmussen KD, Helin K · Blood 2019
   used by KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR, One experiment that decides whether KDM4C is a target or the KDM4 family is: paralogue rescue of SD70 sensitivity in SEM, The dependencies this project keeps failing to see are the buffered ones: paralogue redundancy and guide placement, not absence of biology
3. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31044091
   Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy.

   Wu B, Pan X, Chen X, Chen M, Shi K, Xu J, Zheng J, Niu T, Chen C, Shuai X, Liu Y · Signal Transduction and Targeted Therapy 2019
   used by KDM6A / UTX — a commonly asserted KMT2A partner that belongs to a different complex and points the opposite way
4. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30936419
   Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis.

   Mallaney C, Ostrander EL, Celik H, et al. · Leukemia 2019
   used by KDM6B (JMJD3) - UTX's paralogue, which this graph has argued about for cycles without writing
5. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30624859
   Acute myeloid leukemia with t(10;11)(p11-12;q23.3): Results of Russian Pediatric AML registration study.

   Zerkalenkova E, Lebedeva S, Kazakova A, et al. · Int J Lab Hematol 2019
   used by KMT2A::ABI1 (MLL-ABI1), t(10;11)(p11.2;q23) — the partner that binds an elongation partner
6. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 31599492
   A pediatric case of secondary T-cell acute lymphoblastic leukemia with KMT2A-MAML2 developing after hepatoblastoma treatment.

   Takahashi Y, Terui K, Chinen Y, Tandai S, Kudo K, Sasaki S, Tono C, Taki T, Ito E · Pediatric Blood & Cancer 2019
   used by KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour
7. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30974389
   Ets1 Plays a Critical Role in MLL/EB1-Mediated Leukemic Transformation in a Mouse Bone Marrow Transplantation Model.

   Fu JF, Yen TH, Huang YJ, Shih LY · Neoplasia 2019
   used by KMT2A::MAPRE1 (MLL-EB1) - a coiled-coil dimerisation fusion from pro-B ALL with a mouse model, low leukaemogenic potential, and Ets1 as its effector, MAPRE1 / EB1 (Q15691) - a microtubule plus-end tracking protein that is BOTH a pan-MLL-fusion prey and a genuine KMT2A fusion partner in pro-B ALL
8. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 31128216
   COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer.

   Fagan RJ, Dingwall AK · Cancer Lett 2019
   used by KMT2C (MLL3) - the fetal brake on MLL-rearranged leukaemia, and a 7q tumour suppressor chemotherapy selects against, KMT2D (MLL2/MLL4) - the gene named in this graph's menin-resistance entry, written here for the first time
9. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30028819
   Cryptic ETV6-ABL1 Fusion and MLL2 Truncation Revealed by Integrative Clinical Sequencing in Multiply Relapsed Acute Lymphoblastic Leukemia.

   Mankuzhy NP, Walling E, Anderson B, Mody R · J Pediatr Hematol Oncol 2019
   used by KMT2D (MLL2/MLL4) - the gene named in this graph's menin-resistance entry, written here for the first time, MLL2 and MLL4 each name two different genes, and the ambiguity is in the papers, not in the databases
10. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 30227759
    CDK9: a signaling hub for transcriptional control.

    Bacon CW, D'Orso I · Transcription 2019
    used by LARP7 - the clamp on the 3' end of 7SK, whose human loss-of-function phenotype is dwarfism and intellectual disability rather than cancer, Measure the free-versus-7SK-bound P-TEFb split in KMT2A::AFF1 cells - the experiment this whole beat turns on, which has never been done, What was searched, what came back empty, and what was read and not used - the P-TEFb reservoir beat's audit trail
11. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31136005
    KMT2A (MLL) fusions in aggressive sarcomas in young adults.

    Yoshida A, Arai Y, Tanzawa Y, et al. · Histopathology 2019
    used by LDB1::KMT2A - the clearest statement in this literature that a sarcoma fusion keeps KMT2A exons 4 to 36 and discards exons 1 to 3, VIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon
12. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31405949
    The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development.

    Okeyo-Owuor T, Li Y, Patel RM, Yang W, Casey EB, Cluster AS, Porter SN, Bryder D, Magee JA · Blood Adv 2019
    used by LIN28B has THREE published signs in myeloid leukaemia - oncogene, tumour suppressor, and differentiation agent - and the design quality runs opposite to the direction the index-fusion story needs, PROPOSED: swap the partner, hold everything else - KMT2A::MLLT3 versus KMT2A::AFF1 in LIN28B-null human fetal liver CD34+ cells, PUBLISHED, DONE: human fetal liver CD34+ cells fail to transform on KMT2A::AFF1 induction without LIN28B (Ling et al., Blood 2026) - a dedicated human index-fusion experiment, read from the abstract only, The fetal state is PERMISSIVE for lymphoid KMT2A-fusion transformation and PROTECTIVE against myeloid - which is why LIN28B has opposite signs in the two literatures, The KMT2A::MLLT1 mechanism sweep: what was searched, what was read and not used, and the three retrieval traps that would have produced confident wrong answers, The neonatal window — the state in which an MLL fusion can transform, bounded at both ends, Two groups invoke LIN28B to explain the SAME epidemiological fact in OPPOSITE directions - and neither claim is the one this graph has been repeating
13. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30990684
    Identification of Filamin A Mechanobinding Partner II: Fimbacin Is a Novel Actin Cross-Linking and Filamin A Binding Protein.

    Wang J, Nakamura F · Biochemistry 2019
    used by LUZP1 / fimbacin (Q86V48) - the weakest index-fusion call of the nine, and the strongest non-index call: p = 0.127 against MLL-AF4 and 2.6e-10 against MLL-ENL
14. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31381950
    Fetal liver Mll-AF4+ hematopoietic stem and progenitor cells respond directly to poly(I:C), but not to a single maternal immune activation

    Malouf C, Ottersbach K · Experimental Hematology 2019
    used by Lymphoid-primed multipotent progenitor (LMPP) — the bi-potent cell that explains how one fusion makes two lineages, Multipotent progenitor (MPP) — the stage where the undifferentiated KMT2A-r infant leukaemias map
15. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31104571
    Replication-Independent Histone Turnover Underlines the Epigenetic Homeostasis in Adult Heart.

    Li Y, Ai S, Yu X, et al. · Circulation Research 2019
    used by Measure the clearance clock directly: SNAP-tag H3.3 pulse-chase at KMT2A::AFF1 target genes, with and without DOT1L inhibition, in cycling and arrested cells, The clearance clock has machinery, and the machinery says the clock does NOT stop in a non-dividing cell - a postmitotic heart replaces its histones with a half-life of about two weeks, With no eraser, how fast the histone itself is replaced decides how much H3K79 methylation there is - and that sets the clock a DOT1L drug has to beat
16. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31543346
    Nuclear localization of Meis1 in dermal papilla promotes hair matrix cell proliferation in the anagen phase of hair cycle.

    Namekata M, Yamamoto M, Goitsuka R · Biochem Biophys Res Commun 2019
    used by MEIS1's 'nucleus' is a profile prediction, not a measurement - and a homeodomain-less isoform is cytoplasmic and does the opposite job
17. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29672864
    Menin regulates the serine biosynthetic pathway in Ewing sarcoma.

    Svoboda LK, Teh SSK, Sud S, et al. · The Journal of Pathology 2019
    used by Menin inhibition collapses the serine/one-carbon/ASNS programme in KMT2A::AFF1 cells - PHGDH -3.24, PSAT1 -2.40, ASNS -1.72, flat in a wild-type line - so it should re-sensitise KMT2A-rearranged ALL to asparaginase, a combination PubMed has zero records for, PHGDH (O43175) - the largest menin-SELECTIVE fall in the whole serine panel, and the least essential gene in it, PSPH (P78330) - the third serine-synthesis enzyme, high in Ewing sarcoma alongside PHGDH and PSAT1, and the one that does NOT fall in leukaemia, The one experiment that settles this beat: dose-matched menin and DOT1L arms in RS4;11 with H3K4me3 ChIP at PHGDH, plus 13C-serine flux - and it answers the cycle-58 question at the same time, The serine/one-carbon arm is NOT a pure ATF4 output: it is menin-selective where the ISR arm is compound-independent (median margin -0.55 vs -0.02, p=0.011), and it is ABSENT in KMT2A::MLLT3 AML where the ISR arm is present, The serine/one-carbon programme has a SECOND, chromatin-proximal menin input that is not ATF4 - which is why PHGDH is menin-selective where CHAC1 is not, and why the arm is absent in KMT2A::MLLT3
18. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31467394
    de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation.

    Schneeberger PE, Bierhals T, Neu A, Hempel M, Kutsche K · Sci Rep 2019
    used by MEPCE - absent from this graph until now, and a deeper pan-dependency than BRD4, Raising HEXIM1 to brake the fusion's output without touching the fusion - one supporting experiment, one chemical series, and no therapeutic window, The brake pad is actively thinned: autophagy degrades HEXIM1 in MLL-fusion and NPM1c AML cells
19. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31792411
    Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia

    Granja JM, Klemm S, McGinnis LM, Kathiria AS, Mezger A, et al. · Nature Biotechnology 2019
    used by Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act
20. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30020414
    SKEMPI 2.0: an updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

    Jankauskaite J, Jimenez-Garcia B, Dapkunas J, Fernandez-Recio J, Moal IH · Bioinformatics 2019
    used by Model: interface hotspot prediction - trainable in general, pure extrapolation here, because SKEMPI contains zero menin entries
21. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30930284
    Analysis of histone ubiquitylation by MSL1/MSL2 proteins in vitro

    Krajewski WA, Vassiliev OL · Archives of Biochemistry and Biophysics 666:22-30 2019
    used by MSL1 - the MSL scaffold that carries MOF and MSL2 to HOXA9 and MEIS1, with zero records against KMT2A and a mapped, drawable domain architecture
22. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31597037
    Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

    Kim J, Hu C, Moufawad El Achkar C, et al. · New England Journal of Medicine 2019
    used by N-of-1 and n-of-few: the custom-therapy route, and what it actually costs
23. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31036827
    CUT&Tag for efficient epigenomic profiling of small samples and single cells

    Kaya-Okur HS, Wu SJ, Codomo CA, Pledger ES, Bryson TD, Henikoff JG, Ahmad K, Henikoff S · Nature Communications 10:1930 2019
    used by Neither infant sample has an IgG control, and neither of their two sequencing batches contains one - so every number from this pair is confounded with chromatin accessibility
24. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.datasetPMID 31068700
    Next-generation characterization of the Cancer Cell Line Encyclopedia

    Ghandi M, Huang FW, Jane-Valbuena J, et al. · Nature 569:503-508 2019
    used by No KMT2A-rearranged haematopoietic cell line in CCLE expresses IRX1 - including all four KMT2A::AFF1 lines MV4-11, NALM-19, RS4;11 and SEM at 0.0000-0.0053 RPKM, PROM1/CD133 tracks the HOXA arm and ANTI-tracks the IRX1 arm in 48 KMT2A::AFF1 infant ALL cases - so the one surface target with a published human kill is depleted in the iALL-IRX1 subgroup, RS4;11 (CVCL_0093) — an ADULT KMT2A::AFF1 line, MSI-high, carrying NSD2 E1099K, SEM (CVCL_0095) — the workhorse, from a five-year-old, and microsatellite unstable
25. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 30669574
    NUP214 in Leukemia: It's More than Transport.

    Mendes A, Fahrenkrog B · Cells 2019
    used by NUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions, SET / TAF-Ibeta domain map (Q01105, 290 aa) - dimerisation, earmuff, and the acidic tail that binds MLL, SET::NUP214 (TAF-Ibeta-NUP214, SET-CAN), cryptic del(9)(q34.11q34.13) - a HOXA-driving fusion of a histone chaperone to a nucleoporin, with no KMT2A and no menin-binding motif
26. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30447097
    Identification of genes involved in the regulation of TERT in hepatocellular carcinoma

    Amisaki M, Tsuchiya H, Sakabe T, et al. · Cancer Science 2019
    used by NUTM1 (NUT) - a testis-restricted, fully disordered protein that writes no mark and instead switches ON a writer, and the 3' partner of the KMT2A-wild-type infant B-ALL with the opposite prognosis
27. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 30639603
    Dysregulation of miR-335-3p, targeted by NEAT1 and MALAT1 long non-coding RNAs, is associated with poor prognosis in childhood acute lymphoblastic leukemia

    Pouyanrad S, Rahgozar S, Ghodousi ES · Gene 2019
    used by Paraspeckles and NEAT1 — no KMT2A evidence at all, but a fusion oncoprotein in another leukemia uses NEAT1 as a differentiation brake
28. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30792230
    GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in β cells.

    Xing B, et al. · J Cell Biol 2019
    used by PKA phosphorylates menin at Ser487 and pulls it off chromatin - a kinase input on the drug target itself, SUV39H1 (O43463, KMT1A) - the H3K9me3 writer: a menin effector whose binding region OVERLAPS the drug pocket at its N-terminus, a tumour suppressor in MLL-AF9 AML, recruited to double-strand breaks by CTCF, and never localised at the KMT2A locus in any cell type
29. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
    PDB entries 3KMR (RARalpha ligand binding domain with agonist Am580 and a coactivator fragment), 1DKF (RAR-RXR ligand-binding-domain heterodimer), 1BOR (transcription factor PML, NMR, in the presence of zinc), 2MVW (TRIM19/PML B-box1), 6IMQ (PML B1-box multimers) and 4WJN (SUMO1 in complex with phosphorylated PML)

    RCSB Protein Data Bank · RCSB PDB 2019
    used by PML::RARA, t(15;17)(q24;q21)
30. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31755685
    Optimization of Ligands Using Focused DNA-Encoded Libraries To Develop a Selective, Cell-Permeable CBX8 Chromodomain Inhibitor

    Wang S, Denton KE, Hobbs KF, Weaver T, McFarlane JMB, Connelly KE, Gignac MC, Milosevich N, Hof F, Paci I, Musselman CA, Dykhuizen EC, Krusemark CJ · ACS Chemical Biology 2019
    used by Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1, Polycomb in KMT2A-r leukemia — core PRC2 required, EZH2 and BMI1 dispensable, and CBX8 acting outside its repressive role
31. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31171700
    Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2

    Plys AJ, Davis CP, Kim J, Rizki G, Keenen MM, Marr SK, Kingston RE · Genes & Development 2019
    used by Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1
32. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31853216
    Protein arginine methyltransferase 1 is required for maintenance of normal adult hematopoiesis.

    Zhu L, et al. · International Journal of Biological Sciences 2019
    used by PRMT1 — an MLL-fusion cofactor whose first-in-human inhibitor was terminated for lack of efficacy and toxicity
33. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31417187
    Inhibition of DOT1L and PRMT5 promote synergistic anti-tumor activity in a human MLL leukemia model induced by CRISPR/Cas9.

    Secker KA, Keppeler H, Duerr-Stoerzer S, Schmid H, Schneidawind D, Hentrich T, Schulze-Hentrich JM, Mankel B, Fend F, Schneidawind C · Oncogene 2019
    used by PRMT5 - the type II arginine methyltransferase this graph has reached for sixteen times, whose mark on H3R2 RECRUITS WDR5 to chromatin
34. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30778134
    CD133-directed CAR T-cells for MLL leukemia: on-target, off-tumor myeloablative toxicity.

    Bueno C, ..., Menendez P · Leukemia 2019
    used by PROM1 / CD133 - a direct MLL-AF4 target switched on by an intragenic H3K79me2/3 enhancer, and the one surface target in this disease with a published human-relevant kill
35. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31381561
    PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia.

    Okuyama K, et al. · PLoS Genet 2019
    used by Proximity-interactome beat: every query run, every paper rejected, and the one resource not reachable
36. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31097467
    CtIP is essential for early B cell proliferation and development in mice.

    · J Exp Med 2019
    used by RBBP8 / CtIP - the only unwritten core-complex partner with a DIRECT-interaction record, and the graph already held its mechanism without holding the protein
37. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30818082
    The landscape of chimeric RNAs in bladder urothelial carcinoma

    Zhu D, Singh S, Chen X, Zheng Z, Huang J, Lin T, Li H · International Journal of Biochemistry & Cell Biology 2019
    used by Read-through (cis-SAGe) chimeras: most 'fusions' called from RNA-seq in childhood ALL are normal conjoined genes
38. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30692271
    E3 Ubiquitin Ligases RNF20 and RNF40 Are Required for Double-Stranded Break (DSB) Repair: Evidence for Monoubiquitination of Histone H2B Lysine 120 as a Novel Axis of DSB Signaling and Repair.

    · Mol Cell Biol 2019
    used by RNF40 (BRE1B) — the obligate partner of RNF20, and the one of the pair with a documented link to differentiation and bivalency resolution
39. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30256410
    Mll-COMPASS complexes mediate H3K4me3 enrichment and transcription of the osteoblast master gene Runx2/p57 in osteoblasts

    Rojas A, Sepulveda H, Henriquez B, Aguilar R, Opazo T, Nardocci G, et al. · J Cell Physiol 2019
    used by RUNX2 - a direct KMT2A-chimera target and dependency in T-ALL, a patient-specific enhancer target in KMT2A::AFF1 B-ALL, and the gene a menin inhibitor represses to restore steroid sensitivity in t(4;11) infants
40. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30535390
    AFF3-DNA methylation interplay in maintaining the mono-allelic expression pattern of XIST in terminally differentiated cells.

    Zhang Y, Wang C, Liu X, Yang Q, Ji H, Yang M, Xu M, Zhou Y, Xie W, Luo Z, Lin C · Journal of Molecular Cell Biology 2019
    used by SEC-L3 — the AFF3-scaffolded complex, and the only SEC-family member with a known physiological job: genomic imprinting and X inactivation, The days-long experiment that would close or confirm the imprinting liability: allele-specific XIST and MEG3 readout in cells treated with a YEATS antagonist, The shared reader sits in a complex whose only well-defined normal job is parent-of-origin silencing — and the published safety package for YEATS inhibition is entirely haematopoietic
41. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31285548
    Septin 9 isoforms promote tumorigenesis in mammary epithelial cells by increasing migration and ECM degradation through metalloproteinase secretion at focal adhesions.

    Marcus J, Bejerano-Sagie M, Patterson N, et al. · Oncogene 2019
    used by SEPTIN9 (septin-9 / MSF) — cytoskeletal GTPase, KMT2A fusion partner in t(11;17)(q23;q25)
42. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30767764
    SET SUMOylation promotes its cytoplasmic retention and induces tau pathology and cognitive impairments.

    Qin M; Li H; Bao J; Xia Y; Ke D; Wang Q; Liu R; Wang JZ; Zhang B; Shu X; Wang X · Acta Neuropathol Commun 2019
    used by SET / TAF-I beta - a histone chaperone that binds the retained N-terminus of MLL, co-activates HOXA with it, and is itself a HOXA-activating fusion partner that recruits DOT1L
43. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31235852
    SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness.

    Nguyen CH, Gluxam T, Schlerka A, Bauer K, et al. · Scientific Reports 2019
    used by SOCS2 (O14508) - a MENIN-INHIBITOR-SELECTIVE member of the signature, a cullin-5 E3 substrate receptor, and its likeliest upstream regulator is MEF2C rather than ATF4
44. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30673607
    Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site.

    Yuan Z, VanderWielen BD, Giaimo BD, Pan L, Collins CE, Turkiewicz A, Hein K, Oswald F, Borggrefe T, Kovall RA · Cell Rep 2019
    used by SPEN / SHARP / MINT (Q96T58) - the RNA-binding corepressor that silences the X chromosome, in the pan-MLL-fusion core
45. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31495782
    Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation.

    Viny AD, Bowman RL, Liu Y, Lavallée VP, Eisman SE, Xiao W, Durham BH, Navitski A, Park J, Braunstein S, Alija B, Karzai A, Csete IS, Witkin M, Azizi E, Baslan T, Ott CJ, Pe'er D, Dekker J, Koche R, Levine RL · Cell Stem Cell 2019
    used by STAG2 - the cohesin subunit that defines secondary AML, and the one whose loss a KMT2A fusion does not care about
46. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31694583
    Teetering on a liver's edge: a case report highlighting clinical decision-making in thrombocytopenia

    Yan A, Erdman L, Sung L, Bernstein S · BMC Cancer 2019
    used by Step 1: the blood count and the blood film
47. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31253180
    Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia

    Brzezinka K, Nevedomskaya E, Lesche R, et al. (Stresemann C, senior author) · Journal of Hematology & Oncology 12(1):66 2019
    used by Step 6 — The consequence: self-renewal held on, differentiation never fires, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
48. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30664779
    Small-molecule targeting of brachyury transcription factor addiction in chordoma.

    Sharifnia T, Wawer MJ, Chen T, Huang QY, Weir BA, Sizemore A, et al. · Nat Med 2019
    used by TBXT / brachyury - the notochord master regulator, and one of only two of 102 transcription-factor baits whose neighbourhood contained DOT1L
49. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30833792
    A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.

    Hubel P, et al. · Nat Immunol 2019
    used by TCF7L2 - the protein IntAct's 'DOT1L-TCF4' row is actually about, and the Wnt effector that DOT1L and AF10 coactivate
50. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31410782
    Consolidating the Role of TDP2 Mutations in Recessive Spinocerebellar Ataxia Associated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23).

    Ciaccio C, Castello R, Esposito S, Pinelli M, Nigro V, Casari G, et al. · Cerebellum 2019
    used by TDP2 - the protein-adduct remover named in this graph's own mechanism entry and until now having no entry of its own, TDP2 unglues trapped topoisomerase II from the KMT2A locus - it suppresses translocations overall and manufactures one rare junction class
51. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30728174
    The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia

    Rowe RG, Lummertz da Rocha E, Sousa P, Missios P, Morse M, Marion W, Yermalovich A, Barragan J, et al. · Journal of Experimental Medicine 2019
    used by The age of the marrow, not only the age of the cell, decides whether MLL-rearranged leukaemia comes out myeloid or lymphoid, The neonatal window — the state in which an MLL fusion can transform, bounded at both ends
52. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 31594803
    Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences

    McSwiggen DT, Mir M, Darzacq X, Tjian R · Genes & Development 2019
    used by The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove
53. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30765112
    Mechanism of Cross-talk between H2B Ubiquitination and H3 Methylation by Dot1L.

    Worden EJ, Hoffmann NA, Hicks CW, Wolberger C · Cell 2019
    used by The DOT1L–ubiquitin and DOT1L–acidic-patch interfaces: two non-catalytic surfaces that MV4;11 cells cannot do without, The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
54. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30581117
    Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

    Hao X, Gu H, Chen C, Huang D, Zhao Y, Xie L, Zou Y, Shu HS, et al. · Cell Metabolism 2019
    used by The endosteal niche — the bone surface, where leukaemia-initiating cells were imaged homing and dividing symmetrically, The marrow oxygen gradient — low everywhere, lowest at the sinusoids, and in this leukaemia low oxygen helps the drug rather than the cell
55. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31040182
    The HIRA histone chaperone complex subunit UBN1 harbors H3/H4- and DNA-binding activity.

    Ricketts MD, Dasgupta N, Fan J, et al. · Journal of Biological Chemistry 2019
    used by The HUCA complex (HIRA/UBN1/CABIN1/ASF1a) - four proteins, one job: put H3.3 into chromatin without waiting for S phase, UBN1 - the subunit that decides the HIRA complex is carrying H3.3 and not H3.1, by reading a single glycine
56. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30595549
    Hif-1alpha Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML

    Velasco-Hernandez T, Soneji S, Hidalgo I, Erlandsson E, Cammenga J, Bryder D · Stem Cell Reports 2019
    used by The hypoxic, glycolytic state — the one state that appears independently in leukaemia-initiating cells, in measurable residual disease, and in KMT2A-rearranged B-ALL as a class
57. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
    Cancer Cell Line Encyclopedia (Broad, 2019), ccle_broad_2019_cna, sample MCF7_BREAST: KMT2A (Entrez 4297) = 0, SUV39H1 (6839) = 0, ATM (472) = -2

    Cancer Cell Line Encyclopedia (Broad Institute), served by cBioPortal - study ccle_broad_2019 · cBioPortal for Cancer Genomics 2019
    used by The MCF-7 arm, and the clause that saved it: SUV39H1 at the exon-11 anchor reaches the 96.3rd percentile of 56,171 same-cell-type CTCF anchors in one replicate - but all six non-anchor KMT2A intervals are elevated too (medians 73-87), so the pre-registered FIRES clause does not fire, the verdict is NEITHER, and four replicates of one antibody in one cell line span 51.8 to 96.3 at the same 147 bp
58. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31733991
    Structural Basis of H2B Ubiquitination-Dependent H3K4 Methylation by COMPASS.

    Hsu PL, Shi H, Leonen C, Kang J, Chatterjee C, Zheng N · Mol Cell 2019
    used by The other arm of the crosstalk: H2Bub licenses H3K4 methylation through ASH2L and relieves a built-in COMPASS autoinhibition — and MLL3 does not respond at all
59. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31693904
    Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design

    Rokita JL, Rathi KS, Cardenas MF, et al. · Cell Reports 2019
    used by The PPTC childhood PDX panel — 90 leukaemia models, an MLL-ALL group, and no published partner or age breakdown
60. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31597962
    Decoding human fetal liver haematopoiesis

    Popescu DM, Botting RA, Stephenson E, et al. · Nature 2019
    used by The prevention window: the break happens in a fetus, and we know when it CLOSES but not when it opens
61. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30185131
    Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines.

    Van Schandevyl G, Bauters T · Journal of Oncology Pharmacy Practice 2019
    used by Thiotepa - the third agent that reaches the central nervous system completely, and whose alkylating metabolites are excreted through the skin into a nappy
62. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30692205
    Nuclear pore density controls heterochromatin reorganization during senescence.

    Boumendil C, Hari P, Olsen KCF, Acosta JC, Bickmore WA · Genes Dev 2019
    used by TPR / Megator (P12270) - the nuclear-basket nucleoporin that builds heterochromatin exclusion zones, in the pan-MLL-fusion core
63. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31249361
    The ENCODE Blacklist: Identification of Problematic Regions of the Genome.

    Amemiya HM, Kundaje A, Boyle AP · Scientific Reports 2019
    used by Two processing batches inside one GEO series: the FLAG and KDM2B tracks put 1.7-1.9% of their coverage in ENCODE blacklist regions and the BCOR, RING1B and input tracks put 14-46%, with a single 2 kb bin at chr2:98,666,000 carrying 18.1% of the BCOR SGC0946 track on its own
64. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30773463
    Systematic Dissection of the Metabolic-Apoptotic Interface in AML Reveals Heme Biosynthesis to Be a Regulator of Drug Sensitivity

    Lin KH, Xie A, Rutter JC, Ahn YR, Lloyd-Cowden JM, Nichols AG, Soderquist RS, Koves TR, Muoio DM, MacIver NJ, Lamba JK, Pardee TS, McCall CM, Rizzieri DA, Wood KC · Cell Metabolism 29:1217-1231.e7 2019
    used by UROS: searched and empty — the scan's rank-15 hit has no leukemia literature, and no entry was written
65. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 31804488
    Cryo-EM structure of the human MLL1 core complex bound to the nucleosome.

    Park SH, Ayoub A, Lee YT, et al. · Nat Commun 2019
    used by WDR5 and RBBP5: the second arm of the WRAD hub, RBBP5 V375-D376-V377 into the same propeller face, co-crystallised with the MLL1 WIN peptide in one structure
66. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30625391
    Increased Health Care Utilization and Costs during Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and Myelodysplastic Syndromes in Adolescents and Young Adults Compared with Children: A Multicenter Study

    Rangarajan HG, Smith LC, Stanek JR, et al. · Biology of Blood and Marrow Transplantation 2019
    used by What a transplant costs: about $276,000 for the admission alone
67. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30188223
    Clinicopathologic and genetic spectrum of infantile B-lymphoblastic leukemia: a multi-institutional study

    Knez V, Liu X, Schowinsky J, Pan Z, Wang D, et al. · Leukemia & Lymphoma 2019
    used by Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
68. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30707474
    Acute leukemias harboring KMT2A/MLLT10 fusion: a 10-year experience from a single genomics laboratory

    Peterson JF, Sukov WR, Pitel BA, Smoley SA, Pearce KE, Meyer RG, Williamson CM, Smadbeck JB, Vasmatzis G, Hoppman NL, Greipp PT, Baughn LB, Ketterling RP · Genes Chromosomes Cancer 58:567-577 2019
    used by Which partner, in which patient: KMT2A partner frequencies across six age-lineage strata
69. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30246434
    Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features.

    Andreiuolo F, Varlet P, Tauziède-Espariat A, et al. · Brain Pathol 2019
    used by YAP1 (P46937) - the Hippo pathway's transcriptional co-activator, and a KMT2A fusion partner from a completely different functional class
70. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 31031138
    Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

    Paris J, et al. · Cell Stem Cell 2019
    used by YTHDF2 — the cytoplasmic m6A reader that selectively compromises AML cancer stem cells, discordant across the lineage split here
71. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30679322
    ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms

    Goossens S, Wang J, Tremblay CS, De Medts J, T'Sas S, Nguyen T, Saw J, Haigh K, Curtis DJ, Van Vlierberghe P, Berx G, Taghon T, Haigh JJ · Haematologica 104:1608-1616 2019
    used by ZEB2 — an EMT transcription factor that turns out to be a leukemia dependency and a guardian of lineage fidelity
72. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 31000516
    Cannibalistic acute myeloid leukemia with ZMYND11-MBTD1 fusion

    Plesa A, Sujobert P · Blood 2019
    used by ZMYND11::MBTD1, t(10;17)(p15;q21) - a chromatin reader welded to the NuA4/TIP60 acetyltransferase, maintaining Hoxa/Meis1/Myb/Myc/Sox4 in AML: the KMT2A-fusion architecture built from different parts
73. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29930090
    Imaging dynamic and selective low-complexity domain interactions that control gene transcription

    Chong S, et al. · Science (New York, N.Y.) 2018
    used by 'AF4 bodies' - a named subnuclear compartment that is non-nucleolar and coincident with no known nuclear structure, and the one place a KMT2A fusion has been shown to move a partner, ELL-EAF1: a phosphorylation-gated interface reported to drive phase separation - and the assays used cannot distinguish that from clustered binding, ENL's disordered region and condensates, restricted to what actually bears on KMT2A::MLLT1 - which is one figure panel, EWSR1::FLI1 — the comparator that shows condensate formation has an optimum, and that forcing a fusion into the nucleolus switches it off, NUP98 FG condensates, audited assay by assay: no half-bleach has ever been done and no NUP98 fusion has ever been endogenously tagged, Repairing 85 defective citation blocks, and the finding that the queue's own numbers were wrong in three directions at once, The case that the KMT2A-fusion condensate is an artefact — what 1,6-hexanediol, overexpressed tags and in-vitro droplets actually prove, The only cellular proposal for how the SEC gets P-TEFb out of the reservoir is a condensate, and the two assays it rests on cannot tell that model from its rival
74. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29084774
    LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis.

    El Ashkar S, Schwaller J, et al. · Blood 2018
    used by "Dispensable for haematopoiesis" is a summary of a real phenotype: halved white counts, perturbed HSC and progenitor numbers, and failing serial replating, Expressed, required, maintains — three different claims about where a gene matters, and the graph must label which one it has, Half the menin at fusion-occupied promoters is held by a tether that is not the fusion, LEDGF/p75 is required in the leukaemic cell and dispensable in ADULT MOUSE HAEMATOPOIESIS - not in the normal organism, which its germline knockout does not survive, Menin and LEDGF hold WILD-TYPE KMT2A on chromatin; for the fusion LEDGF is functionally required but positionally dispensable, Menin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled, PSIP1 is a tumour suppressor in the lymphoid lineage next door: losing Psip1 ACCELERATES T-ALL in mice, while the same protein is a dependency in KMT2A-rearranged myeloid leukaemia, Spike-in-normalised menin CUT&RUN in a KMT2A::AFF1 degron line, with replicates and a PSIP1 arm, The experiment that closes the LEDGF hole: doxycycline-inducible PSIP1 knockdown switched on AFTER a human KMT2A::AFF1 xenograft is established, The LEDGF hole, measured: every published LEDGF-removal experiment removes it BEFORE or AT transformation, and none treats an established leukaemia in an animal, The result that runs the wrong way: in Psip1-null cells Hoxa and Hoxd expression goes UP, because Psip1 also recruits Bmi1 and Ctbp1
75. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29777171
    MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity.

    Skucha A, Ebner J, Schmöllerl J, Roth M, et al. (20 authors; Grebien F senior author) · Nature Communications 2018
    used by "Seen in MLL-AF4 and no other bait" excludes AFF1, AFF4 and ELL — the three most AFF1-specific proteins in the experiment — and keeps ACADM and GLUD1, A sharper test than complex enrichment: is the claimed partner's OBLIGATE partner also there? — and its fourth failure is the one protein the source paper named as its own non-selectivity control, ACADM is a mitochondrial matrix beta-oxidation enzyme with an experimentally coded matrix-only localisation, recovered on 8 spectra from a nuclear-extract pulldown whose specific tail is 14.5% mitochondrial — declined, Across all seven MLL-fusion baits, how deep a bait's fixed top-300 list runs into non-significance predicts how many "specific" partners it appears to have — Spearman +0.821, exact p = 0.034, and MLL-AF4 is the extreme on both axes, ACTB / beta-actin (P60709) as a SUBJECT, not a loading control - the dirtiest negative control in the pan-MLL-fusion 42, and the one the paper's authors kept, CEP112 is a 955-residue centrosomal coiled-coil protein on 7 spectra with zero leukaemia literature — its only nuclear annotation is a single 2024 citation, and a long coiled-coil is the classic non-specific AP-MS passenger — declined, CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse, CORRECTED: the AF4-specific interactome gap is ZERO, not one - RPA2 was declined on purpose in cycle 159 and my no-match read was the tool warning I ignored, CSNK2B / CK2beta (P67870) - the regulatory subunit of casein kinase 2, in the pan-MLL-fusion core, with no CSNK2B-and-KMT2A literature at all, DAXX and ATRX are absent from the only MLL-fusion AP-MS interactome - and PML is in it against all seven baits, alone, without a single one of its other body components, DHX16 / hPRP2 (O60231) - the spliceosomal catalytic-activation helicase, pan-MLL-fusion, and one of only two in the 42 whose index-fusion p-value exceeds 0.05, EIF4G1 (Q04637) - a translation-initiation scaffold in the pan-MLL-fusion core, alone, with no other eIF4F subunit anywhere in the 960, ELOA / TCEB3, Elongin A (Q14241) - a Pol II elongation factor in the pan-MLL-fusion core, ALONE, with none of its own complex and a non-zero negative control, Every partner this project imports from the only MLL-fusion AP-MS interactome was pulled from a Strep-HA transgene in Jurkat T-ALL cells — so the host's own lineage factors are in the prey pool, and one of them is LEF1, FTSJ3 (Q8IY81) - the pre-rRNA 2'-O-methyltransferase at the weakest edge of the MLL-fusion nucleolar block: two baits of seven, not the index fusion, and never screened, GLUD1 is a hexameric mitochondrial matrix dehydrogenase recovered on 11 spectra with non-zero control signal from a nuclear pulldown — and this corpus has already declined one KMT2A partner whose sole source was a cryo-EM structure of GLUD1 — declined, GNL2 / Ngp-1 (Q13823) - a nucleostemin-family nucleolar GTPase in the MLL-fusion nucleolar block, in the index fusion's column at p = 0.0492, and the one member with a published granular-component assignment, GPATCH4 (Q5T3I0) - a nucleolar and Cajal-body helicase cofactor in the pan-MLL-fusion core, with no DHX15 and no G-patch relative beside it, JADE3 / PHF16 (Q92613) - the HBO1-complex scaffold with the strongest pan-fusion evidence in this beat, and an independent published contact with MLL, KMT2A::AFF1 has had a published affinity-purification interactome since 2018 — in a paper titled for SETD2, uncurated by IntAct, and cited zero times here, KMT2A::AFF1–LEF1 is one AP-MS row (p 0.0261, 10|8 spectra) in a Jurkat T-ALL host, where LEF1 is a resident lineage factor; it is the only one of the six AF4-specific candidates with non-zero negative-control signal, and no Wnt co-factor was co-recovered — declined, KPNA2 / importin-alpha-1 (P52292) - the classical NLS receptor in the pan-MLL-fusion core, and the ONLY karyopherin of any kind in the whole 960-protein network, LUZP1 / fimbacin (Q86V48) - the weakest index-fusion call of the nine, and the strongest non-index call: p = 0.127 against MLL-AF4 and 2.6e-10 against MLL-ENL, LYAR (Q9NX58) - a zinc-finger nucleolar growth regulator cloned from a T-cell leukaemia line, in six of seven MLL-fusion interactomes, and the one member of this block whose discovery system is the same lineage as the AP-MS host, MAP7D1 (Q3KQU3) - the strongest index-fusion p-value of the nine deferred pan-MLL-fusion preys, on a protein UniProt places entirely outside the nucleus, MAPRE1 / EB1 (Q15691) - a microtubule plus-end tracking protein that is BOTH a pan-MLL-fusion prey and a genuine KMT2A fusion partner in pro-B ALL, MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7, MLL fusions engage NuRD's remodelling arm without its deacetylase arm - and if so, every 'NuRD is repressive' inference in this graph is pointing the wrong way, No orthogonal validation exists for any of the 110 MLL-AF4-specific partners, as far as four declared bounds can see — and the one partner the paper itself followed up, SETD2, is on the opposite list, shared by all seven fusions, Nobody has ever looked at whether a KMT2A fusion is at PML nuclear bodies - a counted zero, with the one biochemical hint pointing yes, NOLC1 / Nopp140 (Q14978) - a nucleolar and Cajal-body phosphoprotein in the pan-MLL-fusion core, and the first physical bridge to this graph's nucleolar convergence, NOP2 / NSUN1 / p120 (P46087) - the 28S rRNA m5C4447 methyltransferase in the MLL-fusion nucleolar block, present in the index fusion's column at p = 0.0223, and the gene whose PubMed token is two-thirds contaminated by its NSUN paralogues, NUDT21 / CFIm25 (O43809) - the CFIm subunit that picks poly(A) sites, in the pan-MLL-fusion core, and a paraspeckle protein, NUP50 / Npap60 (Q9UKX7) - a MOBILE nuclear-basket nucleoporin in the pan-MLL-fusion core, and the evidence says basket, not nuclear envelope, PA2G4 / EBP1 (Q9UQ80) - the best-evidenced member of the MLL-fusion nucleolar block in the index fusion's own column (p = 0.014), and the only one with a published AML phenotype, PES1 / pescadillo (O00541) - the missing PeBoW subunit of this graph's nucleolar block, pan-essential in 96.9% of DepMap lines, and the one myeloid experiment on it shows proliferation WITHOUT a differentiation block, PLANNED: re-search the public PXD009338 raw files for the twelve corepressor subunits the published table truncated away - one compute job that closes twelve measured-not-reported absences and adjudicates the module-split hypothesis, PML / TRIM19 (P29590) - the scaffold of PML nuclear bodies, co-purified with all seven MLL fusions, and never once studied as a KMT2A-fusion partner, PRKAR1A (P10644) - a PKA regulatory subunit in the pan-MLL-fusion core with no catalytic subunit anywhere in the network, and a fusion oncogene in variant APL, PROPOSED: a side-by-side CHD4 co-IP in a t(4;11) B-ALL line and a KMT2A-wildtype B-ALL line, probing one subunit from each NuRD module - the first experiment that would ask whether a KMT2A fusion sees the whole complex, RGPD8 is the top-ranked MLL-AF4-specific prey on 3 spectra, and 96.5% of its tryptic peptides are shared with seven near-identical paralogues — only 4 peptides in the whole protein could ever have discriminated it — declined, RPA2 (RPA32) - the middle subunit of replication protein A, whose disordered N-terminus is the phospho-switch of the replication-stress response and whose 43-171 region binds menin, RPA2 is the only compartment-compatible candidate of the six and the corpus already has a KMT2A resection thread it would fit — but it is an abundant ssDNA-binding subunit on 6 spectra in a benzonase-treated lysate with no RPA1 or RPA3 co-recovered — declined, thread flagged, RRP12 (Q5JTH9) - a pre-40S export factor in six of seven MLL-fusion interactomes but NOT in the index fusion's, and the block's only member with a recessive human disease published in 2025, RRP9 / U3-55K (O43818) - the U3 snoRNP-specific core protein in four MLL-fusion interactomes but NOT the index fusion's, and the block's only member with a published acetylation switch, RSBN1 / KDM9 (Q5VWQ0) - an H4K20me2/me3 demethylase in the AFF4 proximity record, and the only read-queue partner that is a chromatin enzyme at all, SALVAGED from a beat killed by a session limit: the PXD009338 spike control passes decisively, but AFF1 - the index fusion's own partner - has 33 PSMs and ZERO above the identity threshold, so that criterion cannot discriminate any of the six candidates, SCAF11 / SRrp129 (Q99590) - an SR-related protein that binds the RNA Pol II CTD, in the pan-MLL-fusion core, and alone among the SCAF family, SETD2 (Q9BYW2) - the H3K36 trimethyltransferase that binds all seven MLL fusions, and the only one of them with a published KMT2A::AFF1 dependency test, SF3A3 / SF3a60 (Q12874) - a U2 snRNP splicing subunit in the pan-MLL-fusion core, and the paper's own named example of a NON-selective hit, SMARCC1 / BAF155 (Q92922) - the SWI/SNF core scaffold, in the pan-MLL-fusion core, and the missing gene entry in this graph's SWI/SNF beat, SON (P18583) - a nuclear speckle scaffold that BINDS MENIN and inhibits MLL complex assembly, and the one protein in this tranche the Skucha authors name in their own discussion, SPEN / SHARP / MINT (Q96T58) - the RNA-binding corepressor that silences the X chromosome, in the pan-MLL-fusion core, TBL3 / UTP13 (Q12788) - a UTP-B ribosome-biogenesis subunit in the pan-MLL-fusion core, whose loss in zebrafish severely reduces T cells and haematopoietic stem/progenitors, TCOF1 / treacle (Q13428) - the Treacher Collins nucleolar phosphoprotein in the MLL-fusion nucleolar block, the block's only link to rDNA damage signalling through NBS1, and the only member whose loss causes a named human developmental syndrome, The DAXX requirement in B-lineage KMT2A-rearranged lines is a telomere phenotype, not a fusion-target phenotype - and the two non-KMT2A lines in the deep group are the test, The IntAct interactome gap is closed - all 135 'unwritten' interactors are mentioned and 60% carry an explicit decision - while 95 of the 110 partners unique to the INDEX fusion have never been mentioned at all, This repo's "the pan-fusion core is 7.4-fold cleaner per unit signal than the singleton tail" divides one control column by a denominator summed over seven baits — on a per-bait denominator the ratio is 1.06 and p goes from 0.074 to 0.91, Three quarters of KMT2A::AFF1's top partners are shared with other MLL fusions — and the two analyses that said otherwise were both artifacts of how the source table was built, TPR / Megator (P12270) - the nuclear-basket nucleoporin that builds heterochromatin exclusion zones, in the pan-MLL-fusion core, TRIM28 / KAP1 / TIF1beta (Q13263) - the KRAB-ZFP corepressor scaffold in the pan-MLL-fusion core, with the weakest index-fusion p-value but a leukaemic role in another fusion family, UBAP2L (Q14157) - a BMI1-interacting protein essential for haematopoietic stem cell activity, in the pan-MLL-fusion core, and a stress-granule nucleator recovered from NUCLEAR lysate, UTP14A (Q9BVJ6) - an SSU processome component that binds and destabilises p53, in four MLL-fusion interactomes but NOT the index fusion's and below the screen threshold, UTP18 / WDR50 (Q9Y5J1) - the SSU processome subunit that recruits the exosome helicase MTREX to rRNA fragments; in three MLL-fusion interactomes but not the index fusion's, and separately the subject of a 21-year-old IntAct curation error in this graph, VIM / vimentin (P08670) - a pan-MLL-fusion prey with a clean negative control, and separately a genuine KMT2A rearrangement partner in sarcoma, which are two different facts, WBP11 (Q9Y2W2) - a splicing activator in the pan-MLL-fusion core, isolated from its own partners, and a human haploinsufficiency gene, WDR18 (Q9BV38) - the Rix1/PELP1-TEX10-WDR18 60S maturation subunit, in five MLL-fusion interactomes but NOT the index fusion's, and the block's only member whose nucleolar partitioning is SUMO-controlled, WDR33 (Q9C0J8) - the subunit that reads AAUAAA, in the pan-MLL-fusion core, and the plant homolog of which physically links 3' processing to H3K4 demethylation, ZC3H18 (Q86VM9) - the CBC-to-exosome bridge in the pan-MLL-fusion core, and the ONLY member of this tranche whose own complex came with it, ZNF512 (Q96ME7) - the one protein of the nine deferred pan-MLL-fusion preys that is a sequence-specific chromatin factor, and it initiates pericentric heterochromatin
76. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30343899
    Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes.

    Mashtalir N, D'Avino AR, Michel BC, Luo J, et al. · Cell 2018
    used by "SWI/SNF" is three different machines: cBAF, PBAF and ncBAF - and only one of them looks KMT2A-selective
77. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29374058
    Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes.

    Alpsoy A, Dykhuizen EC · J Biol Chem 2018
    used by "SWI/SNF" is three different machines: cBAF, PBAF and ncBAF - and only one of them looks KMT2A-selective, ARID1A (BAF250A) - required in the MLL-AF9 screen, present at the Myc enhancers, and flat in every selectivity measure, ARID2 (BAF200) - the PBAF subunit whose loss ACCELERATES MLL-AF9 leukaemia, and which is nonetheless required to maintain it, BICRA (GLTSCR1) - the ncBAF scaffold, zero PubMed records in KMT2A leukaemia, and a lineage-independent dependency in KMT2A-rearranged lines, DPF2 (BAF45D) - a cBAF-specific reader required in MLL-AF9 cells, with one PubMed record in this disease and no selectivity signal, SS18 - a SWI/SNF subunit that is itself a fusion partner in another cancer, and a lineage-independent dependency in KMT2A-rearranged lines, SWI/SNF split by sub-complex and by lineage: every KMT2A-selective subunit is in the ncBAF module and none is in canonical BAF, The SWI/SNF dependency in KMT2A-rearranged leukaemia belongs to ncBAF, not to canonical BAF - and the drug in the clinic is aimed at the wrong module
78. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30397315
    A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation.

    Michel BC, D'Avino AR, Cassel SH, Mashtalir N, et al. · Nat Cell Biol 2018
    used by "SWI/SNF" is three different machines: cBAF, PBAF and ncBAF - and only one of them looks KMT2A-selective, BICRA (GLTSCR1) - the ncBAF scaffold, zero PubMed records in KMT2A leukaemia, and a lineage-independent dependency in KMT2A-rearranged lines, SMARCB1 (BAF47/INI1/SNF5) - zero entries, zero mentions and, on the evidence, correctly so: it is lost in primary AML rather than required, The SWI/SNF dependency in KMT2A-rearranged leukaemia belongs to ncBAF, not to canonical BAF - and the drug in the clinic is aimed at the wrong module, Two published ways a fusion oncoprotein engages BAF - be a subunit, or recruit it with a disordered domain - and KMT2A has never been tested for either
79. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30503706
    A Transcription Factor Addiction in Leukemia Imposed by the MLL Promoter Sequence

    Lu B, Klingbeil O, Tarumoto Y, Somerville TDD, Huang YH, Wei Y, et al. (Vakoc CR, senior author) · Cancer Cell 34:970-981.e8 2018
    used by 4,589 genes with no prior, and menin comes first (run), ZFP64 — rank 4 on selectivity, and there is not even a ChEMBL entry for it
80. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29997176
    Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation.

    Sharma S, et al. · Proc Natl Acad Sci U S A 2018
    used by 56 of KMT2A's 130 observed phosphosites survive the translocation, and the retained fragment is phospho-denser than the part that is lost, CK2 phosphorylation of KMT2A S136/S142 tunes the LEDGF grip - a second, non-menin, phospho-gated handle on the fragment every fusion keeps, CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology, Enumeration: every phosphorylation-dependent and kinase-regulated contact on KMT2A and its fusions that this beat could find, LEDGF IBD to KMT2A: TWO motifs, not one - IBM1 at 124-133 and IBM2 at 147-152, and the Kd this graph recorded as missing is 14.7 uM, The LEDGF IBD–KMT2A grip: the second half of the clamp, and nobody is drugging it, The second handle on the retained fragment is CK2-dependent, not 14-3-3-dependent, What LEDGF actually does for the fusion: it brings AF4, CDK9, BRD4, P-TEFb and Ser2P Pol II to the target gene, and H4K16ac with them
81. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30125270
    Efficient proximity labeling in living cells and organisms with TurboID.

    Branon TC, et al. · Nat Biotechnol 2018
    used by A BioID hit is a neighbour, not a complex member - and the two methods are known to disagree
82. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29320732
    Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

    Xiu Y, Dong Q, Li Q, Li F, Borcherding N, Zhang W, Boyce B, Xue HH, Zhao C · Cell Rep 2018
    used by A menin inhibitor may release RELA from menin's restraint — and released RELA is what keeps MLL fusions on chromatin. Prior 0.20, Blocking IKK/NF-kB in an infant is removing the switch every immune cell runs on — and the class has already failed clinically on exactly that, Canonical versus non-canonical NF-kB in KMT2A-rearranged leukaemia — the two arms have opposite signs, and the two papers usually read as contradicting each other actually agree, CHUK (IKK-alpha) — the only kinase that sits in BOTH NF-kB arms, which makes it the one subunit whose inhibition has an ambiguous sign in this disease, Is TIFAB a direct RelB target? Two papers in the same MLL-AF9 system answer differently, MAP3K14 (NIK) — the one node in this pathway where ACTIVATION, not inhibition, is the proposed therapy, and the one that also damages normal stem cells, NFKB2 (p100/p52) — menin binds the non-canonical subunit too, and activating that arm SUPPRESSES MLL-AF9 leukaemia, NFKBIA (IkB-alpha) — the switch itself. This graph has entries for everything the switch controls and none for the switch, REL (c-Rel) — the third canonical subunit, measured once and found unchanged, and named in zero papers in this disease, RELB — the NF-kB subunit that SUPPRESSES MLL-AF9 leukaemia, with a direct ChIP target list and a genetic rescue, which makes it the best-evidenced anti-leukaemic node in this beat, The cross-entry contradiction screen does not work, and the reason is that this graph writes carefully, The IKK complex — the unit the eviction experiment actually resolves, because the chemistry that produced the result cannot see the subunits, The NF-kB story in KMT2A-rearranged leukaemia is a myeloid story, and the lymphoid half is not a weaker version of it — it is a different subject, TIFAB — a 161-residue NF-kB adaptor-layer protein with TWO direct KMT2A-fusion papers, which is more disease-specific evidence than any receptor or TRAF in this beat has, TRAF2 - a cytoplasmic NF-kB brake reported as an AFF4 two-hybrid hit, 97 partners in the screen that found it, and the live instance of the brief's own accession trap
83. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29342133
    A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies.

    Bahr C, von Paleske L, Uslu VV, Remeseiro S, Takayama N, Ng SW, et al. · Nature 2018
    used by A noncoding element has no HGNC symbol, so every rule in this brief for resolving an identifier fails on it - worked on the one MYC enhancer that matters, BENC - the MYC blood enhancer cluster 1.7 Mb downstream, required for MLL-AF9 leukaemia maintenance, and named in zero entries of this graph until now, Is BENC even on in the disease this project is about? A module-resolved accessibility and deletion map in KMT2A::AFF1 B-lineage cells, Menin inhibition recruits PRC1 to the BENC MYC enhancer cluster and evicts BRG1, exactly as CBFbeta-SMMHC inhibition does in inv(16), The MYC contradiction can be advanced but not closed: the enhancer is independently validated, the SWI/SNF route is not, and the two papers never measured the same thing
84. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29958106
    CBFbeta-SMMHC Inhibition Triggers Apoptosis by Disrupting MYC Chromatin Dynamics in Acute Myeloid Leukemia

    Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, O'Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH · Cell 2018
    used by A noncoding element has no HGNC symbol, so every rule in this brief for resolving an identifier fails on it - worked on the one MYC enhancer that matters, A time-resolved BRG1/RING1B/H2AK119ub CUT&RUN at BENC under menin inhibition - the inv(16) experiment, run on the right disease, BENC - the MYC blood enhancer cluster 1.7 Mb downstream, required for MLL-AF9 leukaemia maintenance, and named in zero entries of this graph until now, In inv(16), disrupting the fusion interface swaps BRG1 for RING1B at three MYC enhancers - the cleanest version anywhere of the experiment nobody has run on menin, Is BENC even on in the disease this project is about? A module-resolved accessibility and deletion map in KMT2A::AFF1 B-lineage cells, Menin inhibition recruits PRC1 to the BENC MYC enhancer cluster and evicts BRG1, exactly as CBFbeta-SMMHC inhibition does in inv(16), Q50 enumeration: every query this beat ran, every zero it recorded with its bound, and the papers it read and did not use, The MYC contradiction can be advanced but not closed: the enhancer is independently validated, the SWI/SNF route is not, and the two papers never measured the same thing, There is no selective PRC1 catalytic inhibitor - the entire chemistry is one 2013 tool compound and its analogues, and it hits both paralogues by design
85. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 30423293
    A CHAF1B-Dependent Molecular Switch in Hematopoiesis and Leukemia Pathogenesis

    Volk A, ..., Crispino JD · Cancer Cell 2018
    used by A null that costs one command, run first rather than afterwards - and SSRP1 is genuinely LESS required in KMT2A-rearranged lines, while the rest of the chaperone layer is not much of anything, CHAF1B (CAF-1 p60) - the one histone chaperone in this beat with a real leukaemia literature, and a mouse experiment that contradicts DepMap's verdict on its druggability, Is any histone chaperone selectively required in KMT2A-rearranged leukaemia? Twenty-nine genes, lineage-split - and the answer is no, with one number worth a null and a positive tail nobody expected
86. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29276034
    DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants.

    Xu C, Liu K, Lei M, et al. · Structure 2018
    used by A sixth paper systematically measured every human CXXC domain's DNA binding, deposited the MLL co-crystal, and failed all five retrieval routes, CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, CXXC to unmethylated CpG DNA: nine mapped contact residues, and an affinity that spans 44 uM to 33 nM depending on the construct, the DNA and the salt, Degrade one CXXC reader, ChIP the fusion: the one experiment that settles whether the address is contested, DNMT1 - the antagonist: its CXXC domain reads unmethylated CpG in order to STOP methylation, and it is the only heterologous CXXC that runs an MLL-AF9 leukaemia, FBXL19 - a CpG-island reader that delivers CDK-Mediator and RNF20 to developmental promoters, and whose experimental localisation is mostly cytoplasm, MBD1 - one protein with a methyl-CpG reader and three CXXC fingers, only the third of which binds unmethylated CpG, and whose CXXC fails the MLL-AF9 swap, TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away, The human CXXC/CpG-reading family is exactly twelve proteins, and TET2 is not one of them
87. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
    PXD009338 - Protein Interactions of 7 MLL-fusion Proteins (sample-processing and data-processing protocols)

    Skucha A, et al., deposited via PRIDE 2018-04-23, public 2018-05-25 · ProteomeXchange / PRIDE, EMBL-EBI 2018
    used by ACADM is a mitochondrial matrix beta-oxidation enzyme with an experimentally coded matrix-only localisation, recovered on 8 spectra from a nuclear-extract pulldown whose specific tail is 14.5% mitochondrial — declined, Every partner this project imports from the only MLL-fusion AP-MS interactome was pulled from a Strep-HA transgene in Jurkat T-ALL cells — so the host's own lineage factors are in the prey pool, and one of them is LEF1, KMT2A::AFF1 has had a published affinity-purification interactome since 2018 — in a paper titled for SETD2, uncurated by IntAct, and cited zero times here, PLANNED: re-search the public PXD009338 raw files for the twelve corepressor subunits the published table truncated away - one compute job that closes twelve measured-not-reported absences and adjudicates the module-split hypothesis, RGPD8 is the top-ranked MLL-AF4-specific prey on 3 spectra, and 96.5% of its tryptic peptides are shared with seven near-identical paralogues — only 4 peptides in the whole protein could ever have discriminated it — declined, RPA2 is the only compartment-compatible candidate of the six and the corpus already has a KMT2A resection thread it would fit — but it is an abundant ssDNA-binding subunit on 6 spectra in a benzonase-treated lysate with no RPA1 or RPA3 co-recovered — declined, thread flagged, The junction-peptide absence was a claim about mass-spectrometry datasets bounded by a PubMed abstract search: PRIDE holds three human MLL-AF4 proteomics projects, so measured-not-searched is now named rather than asserted
88. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29925947
    Nuclear ARP2/3 drives DNA break clustering for homology-directed repair.

    Schrank BR, Aparicio T, Li Y, Chang W, Chait BT, Gundersen GG, Gottesman ME, Gautier J · Nature 2018
    used by ACTB / beta-actin (P60709) as a SUBJECT, not a loading control - the dirtiest negative control in the pan-MLL-fusion 42, and the one the paper's authors kept
89. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29288530
    PKA-binding domain of AKAP8 is essential for direct interaction with DPY30 protein.

    Bieluszewska A, Weglewska M, Bieluszewski T, Lesniewicz K, Poreba E · FEBS J 2018
    used by AKAP8 (AKAP95) - the only nuclear A-kinase anchoring protein, and the one that turned out to be required for MLL-rearranged leukaemia, AKAP95-DPY30: a direct contact whose binding determinant two groups map to OPPOSITE ends of AKAP95, and neither has been structurally resolved
90. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30244833
    Examining the Roles of H3K4 Methylation States with Systematically Characterized Antibodies.

    Shah RN, Grzybowski AT, Cornett EM, Johnstone AL, et al. · Mol Cell 2018
    used by An assay that cannot separate me2a from me2s cannot test the arginine switch - the two states are isobaric and predict OPPOSITE things, so a non-discriminating readout returns no information rather than an imprecise answer, Arginine methylation gates KMT2-complex access to chromatin at two residues, in both directions, independently of the menin tether AND of the WIN motif - a parallel control point, not a rival to menin dependence, H3R2me2a - the asymmetric arginine mark two residues from H3K4 that LOCKS the WRAD module off the histone tail, and the first arginine mark node in this graph, H3R2me2s - the symmetric mark on the SAME residue as H3R2me2a, which permits rather than enhances WRAD access, and whose 'enhancing' half this graph inherited from the paper that was later revised
91. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30232013
    Genomic Location of PRMT6-Dependent H3R2 Methylation Is Linked to the Transcriptional Outcome of Associated Genes.

    Bouchard C, Sahu P, Meixner M, Nötzold RR, et al. · Cell Rep 2018
    used by Arginine methylation gates KMT2-complex access to chromatin at two residues, in both directions, independently of the menin tether AND of the WIN motif - a parallel control point, not a rival to menin dependence, H3R2me2a - the asymmetric arginine mark two residues from H3K4 that LOCKS the WRAD module off the histone tail, and the first arginine mark node in this graph, H4R3me2a - the activating arginine mark that a KMT2-family enzyme's OWN tandem PHD module reads, where the Kabuki-syndrome mutations sit, and which no KMT2A-fusion study has ever measured, Measure H3R2 and H4R3 methylation states at KMT2A-fusion targets by isomer-resolving mass spectrometry, and test the gate by writer perturbation read out on the enzyme's product - the experiment that has never been done in any fusion, PRMT6 - the enzyme whose mark is MUTUALLY EXCLUSIVE with the MLL complex on the H3 tail, and which shuts HOX genes down by evicting WDR5
92. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29482581
    The chromatin remodeling subunit Baf200 promotes normal hematopoiesis and inhibits leukemogenesis.

    Liu L, Wan X, Zhou P, Zhou X, et al. · J Hematol Oncol 2018
    used by ARID1A (BAF250A) - required in the MLL-AF9 screen, present at the Myc enhancers, and flat in every selectivity measure, ARID2 (BAF200) - the PBAF subunit whose loss ACCELERATES MLL-AF9 leukaemia, and which is nonetheless required to maintain it
93. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30270175
    Structural Analysis of the Ash2L/Dpy-30 Complex Reveals a Heterogeneity in H3K4 Methylation.

    Haddad JF, Yang Y, Takahashi YH, Joshi M, Chaudhary N, Woodfin AR, Benyoucef A, Yeung S, Brunzelle JS, Skiniotis G, Brand M, Shilatifard A, Couture JF · Structure 2018
    used by ASH2L — the WRAD subunit that has DPY30's essentiality profile and none of its co-dependency signal, ASH2L: the only WRAD subunit ever perturbed in a KMT2A::AFF1 cell, once, weakly, Do the other WRAD subunits behave like DPY30? (run, not planned), DPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency, DPY30 aims the H3K4 machinery while ASH2L powers it, which is why only DPY30 tracks menin, DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose, Separate positioning from catalysis: an ASH2L mutant that keeps RBBP5 and loses DPY30
94. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29724899
    The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

    Stein EM, Garcia-Manero G, Rizzieri DA, et al. · Blood 2018
    used by At low drug doses the leukaemia dies through FLT3, not through HOXA9 - a second H3K79me2 pathway the dose-response hides, Blocking where DOT1L binds instead of what it does - the modality that removes the mark only at fusion targets, Bounding an absence the graph already asserts: the H3K79me2 decay half-life, counted, dated and controlled - and why three of the six hits are about the drug's half-life, DOT1L and H3K79 in KMT2A::MLLT1: a direct partner contact, mutually exclusive with the elongation complex, and the only fusion with a DOT1L-inhibitor complete remission, DOT1L and H3K79 in KMT2A::MLLT3: recruitment is a graded dial that sets methylation and transformation - and the fusion it was discovered in produced no remission in the DOT1L trial, DOT1L was not refuted - the wrong thing was blocked, at a dose nobody finished escalating, DOT1L808 - a 5 nM DOT1L degrader that cleared an orthotopic leukaemia and still works after menin inhibitors fail, H3K79me1 - the first methyl group, the one H2B ubiquitination is not needed for, and the state HOX loci fall back to as blood cells mature, H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of, H3K79me2 builds up as B cells mature - so in B-ALL the drug's target is what the rescued compartment runs on, How much sugar the cell has decides how much DOT1L there is - a metabolic dial on the leukaemia's mark, KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3), MAT2A - the enzyme that makes the methyl donor, and the one metabolic dependency in this disease with two independent papers and a lymphoid PDX result, Measure the clearance clock directly: SNAP-tag H3.3 pulse-chase at KMT2A::AFF1 target genes, with and without DOT1L inhibition, in cycling and arrested cells, Nobody has convincingly found the H3K79 eraser - and that constraint sets the clock on every DOT1L inhibitor, Normal blood needs DOT1L too - lose it in an adult mouse and the marrow fails within weeks, Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field, Step 4 — The histone mark: DOT1L and H3K79me2/3 at fusion target genes (and why global expression barely moves), The transfer rule: which MLL-AF9 results can be carried into t(11;19) and t(4;11), and which are statements about a protein missing a reading module, Under EPZ5676 the canonical KMT2A-fusion targets look like they lose H3K79me2 far more than the genome (p=0.017 and p=0.0004), and against a baseline-matched null the entire effect vanishes (p=0.34 and p=0.22) - eight of the ten are simply top-decile genes, Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain, With no eraser, how fast the histone itself is replaced decides how much H3K79 methylation there is - and that sets the clock a DOT1L drug has to beat
95. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30266823
    Inhibition of MEK and ATR is effective in a B-cell acute lymphoblastic leukemia model driven by Mll-Af4 and activated Ras.

    Chu SH, Song EJ, Chabon JR, Minehart J, Matovina CN, Makofske JL, et al. · Blood Adv 2018
    used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it, Mll-AF4 mouse genetics — B-lineage tumours, long latency, and never infant pro-B ALL, Multipotent progenitor (MPP) — the stage where the undifferentiated KMT2A-r infant leukaemias map
96. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
    First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL)

    GlaxoSmithKline · ClinicalTrials.gov 2018
    used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, PRMT1 — an MLL-fusion cofactor whose first-in-human inhibitor was terminated for lack of efficacy and toxicity
97. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30370956
    A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease

    See PubMed record PMID 30370956 for the full author list (not transcribed here) · American Journal of Hematology 2018
    used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, CDK9 inhibition in KMT2A-rearranged infant leukemia — the most direct hit on the hijacked machinery, and the narrowest window, The bite-back of striking a target: a wrong strike costs a cure and generates no data that it was wrong, The phase-2 go/no-go register: the numbers we agree to before we look
98. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29431698
    MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

    Brown FC, Still E, Koche RP, et al. · Cancer Discovery 2018
    used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of, The phase-2 go/no-go register: the numbers we agree to before we look
99. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29466156
    Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children

    Drilon A, Laetsch TW, Kummar S, et al. · New England Journal of Medicine 2018
    used by Basket and umbrella designs: pooling rare fusions into one trial, ETV6::NTRK3 (ETV6-TRKC), t(12;15)(p13;q25), Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), TRK inhibitors: one drug, seventeen cancers, and a paediatric population that actually got dosed
100. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29748211
     Antileukemic Efficacy of BET Inhibitor in a Preclinical Mouse Model of MLL-AF4+ Infant ALL

     Bardini M, Trentin L, Rizzo F, et al. · Molecular Cancer Therapeutics 2018
     used by BET bromodomain inhibition in KMT2A-rearranged leukemia — spectacular preclinically, stalled clinically
101. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29937342
     Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2.

     Higgs MR, Sato K, Reynolds JJ, Begum S, Bayley R, Goula A, Vernet A, Paquin KL, Skalnik DG, Kobayashi W, Takata M, Howlett NG, Kurumizaka H, Kimura H, Stewart GS · Mol Cell 2018
     used by BOD1L (BOD1L1) — the top SETD1A co-dependency, and the only candidate in this cycle tested by CRISPR tiling in a KMT2A::AFF1 line, Replication stress and interstrand-crosslink repair as a cell state - an ATR dependency measured in mouse MLL-rearranged AML, and the same stress implicated in breaking the MLL locus in the first place
102. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30381403
     Recurrent CCND3 mutations in MLL-rearranged acute myeloid leukemia.

     Matsuo H, Yoshida K, Fukumura K, Nakatani K, Noguchi Y, Takasaki S, Noura M, Shiozawa Y, Shiraishi Y, Chiba K, Tanaka H, Okada A, Nannya Y, Takeda J, Ueno H, Shiba N, Yamato G, Handa H, Ono Y, Hiramoto N, Ishikawa T, Usuki K, Ishiyama K, Miyawaki S, Itonaga H, Miyazaki Y, Kawamura M, Yamaguchi H, Kiyokawa N, Tomizawa D, Taga T, Tawa A, Hayashi Y, Mano H, Miyano S, Kamikubo Y, Ogawa S, Adachi S · Blood Adv 2018
     used by Bounded failure: the CDK4/6 cell lines behind two therapeutic entries are unrecoverable although the article is marked free access, CCND3 (cyclin D3) — the scan's rank-4 hit, and the only one of the four with a drug class already in children, CDK4/6 inhibition in KMT2A-rearranged leukemia — the class was already tried, and the trial never reported, The G1 state in KMT2A-rearranged leukaemia — where CDK6 does a job that is not about the cell cycle at all
103. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28701730
     The MLL recombinome of acute leukemias in 2017

     Meyer C, Burmeister T, Gröger D, et al. · Leukemia 2018
     used by Breakpoint anatomy, and an audit of the prognosis claim, Each partner prefers a different KMT2A exon: partner-specific break position in 3,401 patients, Hypothesis: the KMT2A breakpoint map is shaped by product viability, not only by DNA fragility, and the signature is that breaks respect inter-domain linkers, Hypothesis: the KMT2A genomic breakpoint carries prognostic information that the field has been sitting on for twenty years, Is reciprocal status or breakpoint position used in MRD design or risk stratification? Once, by necessity, in 16 of 3,401 patients - and nowhere in any risk model, Is the YEATS asymmetry just intron geometry? Computed from hg38: the direction is explained, the magnitude is not, and both genes fail the same prediction, Join the KMT2A breakpoint archive to the Interfant MRD and outcome database, on patient, MLLT3 is the commonest partner in therapy-induced KMT2A leukaemia: 49 of 142, and 47 of those are t-AML, MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction, Rolf Marschalek & Claus Meyer (DCAL, Goethe-University Frankfurt) — the world's KMT2A breakpoint dataset, Step 3: the G-banded karyotype and t(4;11)(q21;q23), The YEATS asymmetry is breakage geography, not selection: the reader's fate is decided by where topoisomerase II cuts, before any leukaemia exists, Where t(9;11) actually breaks inside MLLT3: 98.4% downstream of exon 4, and the two patients in 442 who kept the reader
104. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29399859
     Hyperleukocytosis in infant acute leukemia: a role for manual exchange transfusion for leukoreduction.

     Runco DV, Josephson CD, Raikar SS, Goldsmith KC, Lew G, Pauly M, et al. · Transfusion 2018
     used by Bringing down a white count of half a million in a four-kilogram baby
105. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29193219
     Therapeutic leukocytapheresis in infants and children with leukemia and hyperleukocytosis: A single institution experience.

     Thapa N, Pham R, Cole C, Meinershagen M, Bowman PW, Ray A · J Clin Apher 2018
     used by Bringing down a white count of half a million in a four-kilogram baby, WBC 300: a stratification convenience, not a biological threshold - and the evidence says so four different ways
106. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29894694
     CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis.

     Greenblatt SM, Man N, et al. · Cancer Cell 2018
     used by CARM1 / PRMT4 (Q86X55) - the H3R17me2a writer, and the enzyme whose product is read by the KMT2A C-terminus that every fusion deletes
107. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 30592296
     CBFA2T3-GLIS2-positive acute myeloid leukaemia. A peculiar paediatric entity

     Masetti R, Bertuccio SN, Pession A, Locatelli F · Br J Haematol 2018
     used by CBFA2T3::GLIS2, inv(16)(p13.3q24.3)
108. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30312172
     H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions.

     Svobodová Kovaříková A, et al. · Aging (Albany NY) 2018
     used by CBX1 / HP1-beta (P83916, 185 aa) - the HP1 paralogue with the fitness cost and no role in this graph's cascade: DepMap mean -0.349 with 16.6% of 1,257 lines below -0.5, four times deeper than HP1-gamma or HP1-alpha, and zero papers place it anywhere near KMT2A, The HP1 paralogue asymmetry is a guide-cross-reactivity artefact until somebody shows it is not - and if it is real, HP1-beta is doing a job the other two cannot, which is the only HP1 question in this graph with a fitness phenotype attached
109. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30104252
     CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum.

     Bagashev A, Sotillo E, Tang CH, Black KL, Perazzelli J, Seeholzer SH, Argon Y, Barrett DM, Grupp SA, Hu CC, Thomas-Tikhonenko A · Mol Cell Biol 2018
     used by CD19 - the molecule this disease is treated by, named in 114 entries and written in none of them until now, The plasma membrane - the one compartment this graph targets with drugs and had never written down
110. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29593094
     Distinct human alpha(1,3)-fucosyltransferases drive Lewis-X/sialyl Lewis-X assembly in human cells

     Mondal N, ..., Sackstein R · Journal of Biological Chemistry 2018
     used by CD65s has no known synthesising enzyme, and the three fucosyltransferases nearest to it are explicitly excluded
111. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28945229
     The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia.

     Serio J, Ropa J, Chen W, Mysliwski M, Saha N, Chen L, Wang J, Miao H, Cierpicki T, Grembecka J, Muntean AG · Oncogene 2018
     used by CDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion, H4R3me2s - the repressive symmetric arginine mark that recruits DNMT3A, blocks a KMT2 enzyme's own PHD module, and is the ONLY arginine mark ever measured in a KMT2A-fusion system, Measure H3R2 and H4R3 methylation states at KMT2A-fusion targets by isomer-resolving mass spectrometry, and test the gate by writer perturbation read out on the enzyme's product - the experiment that has never been done in any fusion, PRMT1 — an MLL-fusion cofactor whose first-in-human inhibitor was terminated for lack of efficacy and toxicity, PRMT3 - the mostly-cytoplasmic ribosome methyltransferase that also writes the ACTIVATING mark on the residue PRMT5 represses, has an acute-leukaemia degrader, and is invisible to this project's own mark-query rule, PRMT5 - the type II arginine methyltransferase this graph has reached for sixteen times, whose mark on H3R2 RECRUITS WDR5 to chromatin
112. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29774127
     PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression of Hoxa9 and Meis1 in acute myeloid leukemia.

     Ropa J, Saha N, Chen Z, Serio J, Chen W, Mellacheruvu D, Zhao L, Basrur V, Nesvizhskii AI, Muntean AG · Oncotarget 2018
     used by CDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion, H3K9me3 - measured in KMT2A::AFF1 cells, in a supplementary figure, and it rises GENERALLY where H3K27ac falls SPECIFICALLY in the same experiment, PAF1 — pan-essential subunit of a complex the fusion needs, where the window is in the interface and not in the protein, SETDB1 (Q15047, KMT1E/ESET) - the second H3K9me3 writer: it represses the fusion's own targets via the PAF1 complex, it is required in fetal liver HSPCs and in leukaemic stem cells, and it is a broad dependency in half the CRISPR panel - three published directions that do not agree
113. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     A Phase I Study of Palbociclib in Combination With Chemotherapy in Pediatric Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

     St. Jude Children's Research Hospital · ClinicalTrials.gov 2018
     used by CDK4/6 inhibition in KMT2A-rearranged leukemia — the class was already tried, and the trial never reported, COG AINV18P1 (NCT03792256) — palbociclib is deliverable in children with relapsed ALL, at 50 mg/m² for 21 days
114. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29453291
     LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPalpha-dependent enhancers in AML

     · Blood 2018
     used by CEBPA — ranks 25th on the KMT2A scan and sits at the median of random genes, SPI1 / PU.1 — a myeloid dependency that a KMT2A panel mistakes for its own
115. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28943635
     NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL

     Prieto C, Lopez-Millan B, Roca-Ho H, et al. · Leukemia 2018
     used by Central nervous system involvement at diagnosis in KMT2A-rearranged infant leukaemia, CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it, Experiment: where do KMT2A::AFF1 blasts go when a menin inhibitor releases the block? Single-cell lineage destination under drug, Fetal CD19+CD34+CD10-negative PreProB progenitor — a cell that exists before birth and almost not at all after, KRAS as a co-mutation in KMT2A-r leukemia — the single most frequently co-mutated gene, and it still cannot start the disease, Measure the RAS allele fraction in CSF blasts and in paired marrow blasts from the same infant on the same day, NG2 is absent from the candidate leukaemia stem-cell populations in t(4;11) ALL and 11q23 AML, so an NG2-directed therapy would debulk the disease and leave the fraction that initiates relapse, NG2 reads the fusion's transcriptional programme, not the DNA lesion - so a menin inhibitor should erase the graph's best diagnostic marker while the rearrangement stays put, Pro-B cell — the stage at which KMT2A::AFF1 leukaemia is arrested, and the phenotype the diagnosis is made on, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there, Treat a KMT2A::AFF1 patient-derived xenograft with an NG2-directed agent and read out the CD34+CD19-CD117+ fraction at nadir - does the reservoir the 2006 flow data predicts actually survive?
116. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29599201
     The chromatin-remodeling factor CHD4 is required for maintenance of childhood acute myeloid leukemia.

     Heshmati Y, Turkoz G, Harisankar A, Kharazi S, Bostrom J, et al. · Haematologica 2018
     used by CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse
117. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30077013
     Epitope mapping of anti-ALK antibodies in children with anaplastic large cell lymphoma.

     Knorr F, Weber S, Singh VK, Pulford K, Reiter A, Woessmann W, Damm-Welk C · Clin Immunol 2018
     used by Children with NPM1::ALK lymphoma immunise themselves against their own fusion protein, and the antibody titre predicts relapse - while no autoantibody against any KMT2A fusion has ever been reported. The difference is not the junction; it is that ALK is an ectopic self-antigen and KMT2A and AFF1 are not.
118. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 29642597
     Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma.

     Stadler S, Singh VK, Knorr F, Damm-Welk C, Woessmann W · Cancers (Basel) 2018
     used by Children with NPM1::ALK lymphoma immunise themselves against their own fusion protein, and the antibody titre predicts relapse - while no autoantibody against any KMT2A fusion has ever been reported. The difference is not the junction; it is that ALK is an ectopic self-antigen and KMT2A and AFF1 are not.
119. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29578410
     A conserved function for pericentromeric satellite DNA

     Jagannathan M, Cummings R, Yamashita YM · eLife 2018
     used by Chromocentres and pericentromeric satellite heterochromatin — no KMT2A evidence, but the AT-hook argument says there should be
120. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28939057
     The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability.

     Grey W, et al. · Biochim Biophys Acta Mol Cell Res 2018
     used by Cks1 and Cks2 hold both halves of KMT2A and set its level through the cell cycle, SCF(Skp2) grips the retained fragment and the fusion escapes it - the clearest documented non-menin contact on that region
121. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29425493
     Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity.

     Kurmi K, Hitosugi S, Wiese EK et al · Cell Reports 2018
     used by CPT1A - the outer-mitochondrial-membrane fatty-acid gatekeeper that is also a lysine succinyltransferase, fused to KMT2A exon 3 in the one case that is tether WITHOUT address
122. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29905868
     Casein kinase 2 mediated phosphorylation of Spt6 modulates histone dynamics and regulates spurious transcription.

     Gouot E, Bhat W, Rufiange A, et al. · Nucleic Acids Res 2018
     used by CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology
123. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29227476
     The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

     Bolouri H, Farrar JE, Triche T, et al. · Nature Medicine 2018
     used by DNMT3A - an independent adverse factor in adult KMT2A-rearranged AML and conspicuously absent from paediatric disease, which is the whole finding, ELF1 - a direct transcriptional target of MLL fusion proteins and HOXA9 that is ALSO a BioID neighbour of KMT2A, and that is focally deleted in paediatric AML without a KMT2A rearrangement, NCI TARGET — a finished paediatric leukaemia genomics resource, not an active partner, No second driver means no second target - the quiet genome forecloses the combination logic that works in every other leukaemia, PTPN11 in KMT2A-r leukemia — named in every gene list, supported by almost no cases, TP53 - named in 84 entries of this graph, absent from the index genome study of the disease, and four different things depending on when you look
124. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
     PDB entry 6E8C: Crystal structure of the double homeodomain of DUX4 in complex with DNA; RCSB search on UniProt Q9UBX2 returns 11 entries (5Z2S, 5Z2T, 5Z6Z, 5ZFW, 5ZFY, 5ZFZ, 6A8R, 6DFY, 6E8C, 6U81, 6U82)

     RCSB Protein Data Bank · RCSB PDB 2018
     used by DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus
125. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29379173
     Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes.

     Poepsel S, Kasinath V, Nogales E · Nat Struct Mol Biol 2018
     used by EED - the PRC2 subunit this disease actually needs, with drugs in the clinic and zero leukaemia studies, H3K27me3 - the repressive mark this graph argued about for seventy-seven cycles without ever writing an entry for it, PRC2 - the complex, not the subunit, is the unit every experiment in this disease actually resolves
126. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30089904
     Genetic and transcriptional evolution alters cancer cell line drug response.

     Ben-David U, Siranosian B, et al. · Nature 2018
     used by Eleven immortalised lines passaged for decades: the competing explanation this beat could not close
127. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30008805
     An uncommon t(9;11)(p24;q22) with monoallelic loss of ATM and KMT2A genes in a child with myelodysplastic syndrome/acute myeloid leukemia who evolved from Fanconi anemia.

     Lovatel VL, de Souza DC, et al. · Mol Cytogenet 2018
     used by Eleven immortalised lines passaged for decades: the competing explanation this beat could not close
128. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 29332244
     Structural insights into the function of Elongator.

     Dalwadi U, Yip CK · Cell Mol Life Sci 2018
     used by ELP1 (IKBKAP/IKAP) - the Elongator scaffold that was first named for the IKK complex, is a paediatric-cancer predisposition gene, and has an RNA Pol II contact in IntAct, ELP2 (STATIP1/StIP1) - the double beta-propeller of the Elongator core, whose informal name collides with a different human gene and whose STAT3 function is a by-similarity annotation, ELP3 - the catalytic subunit, the only Elongator protein with a real acetyltransferase domain, and the one whose loss in mouse blood causes marrow failure and then p53-mutant leukaemia, ELP4 (PAXNEB) - a required subunit of Elongator, the one partner of the seven with a genuine histone-acetyltransferase connection, and the one whose fusion supplies only its last 43 residues
129. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29415125
     Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.

     Bento-Abreu A, Jager G, et al. · Hum Mol Genet 2018
     used by ELP3 - the catalytic subunit, the only Elongator protein with a real acetyltransferase domain, and the one whose loss in mouse blood causes marrow failure and then p53-mutant leukaemia
130. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29531323
     Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression.

     McClure BJ, Heatley SL, Kok CH, Sadras T, An J, Hughes TP, et al. · Br J Cancer 2018
     used by EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase
131. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29606586
     Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study

     Laetsch TW, DuBois SG, Mascarenhas L, et al. · Lancet Oncology 2018
     used by ETV6::NTRK3 (ETV6-TRKC), t(12;15)(p13;q25), Hypothesis: the paediatric gap is set by the population ratio, not by paediatric biology, TRK inhibitors: one drug, seventeen cancers, and a paediatric population that actually got dosed
132. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29581585
     The dTAG system for immediate and target-specific protein degradation

     Nabet B, Roberts JM, Buckley DL, et al. (Bradner JE, senior author) · Nature Chemical Biology 14(5):431-441 2018
     used by Experiment: build the missing KMT2A::AFF1 degron and titrate it — what fractional occupancy does the program actually need?, Reversibility and kinetics — does the program collapse when the fusion is removed, and how fast?
133. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29438697
     Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.

     Booth CAG, Barkas N, Neo WH, Boukarabila H, Soilleux EJ, Giotopoulos G, et al. · Cancer Cell 2018
     used by EZH2 - the Polycomb enzyme that collaborates with the fusion instead of opposing it, and that no single-agent inhibitor can switch off
134. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29809150
     FBXL19 recruits CDK-Mediator to CpG islands of developmental genes priming them for activation during lineage commitment.

     Dimitrova E, Kondo T, et al. · Elife 2018
     used by FBXL19 - a CpG-island reader that delivers CDK-Mediator and RNF20 to developmental promoters, and whose experimental localisation is mostly cytoplasm
135. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29284596
     Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL.

     Wood B, Wu D, Crossley B, et al. · Blood 2018
     used by Flow-cytometric MRD: the fastest readout, and the one a lineage switch walks straight out of, Ig-based MRD fails specifically in the KMT2A-rearranged patients whose IGH repertoire is proximally biased and still recombining, MRD as a trial endpoint in KMT2A-rearranged leukaemia: high negativity rates, and almost none of them say which assay, Sequencing-based MRD: better than flow in paediatric B-ALL, and applied to infant KMT2A-rearranged disease exactly once, The MRD target a centre can run decides which infants are intensified, and the two targets disagree in the direction that matters, What MRD-negative actually means: a quantitative range, a laboratory judgement, and three incompatible definitions
136. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29898879
     Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL.

     Wölfl M, Rasche M, Eyrich M, et al. · Blood Adv 2018
     used by Flow-cytometric MRD: the fastest readout, and the one a lineage switch walks straight out of, Hypothesis: releasing the KMT2A::AFF1 differentiation block sends cells toward myeloid, not mature B, in a measurable fraction of infant cases, Lineage switch as a menin-inhibitor escape route — documented in a patient on revumenib, and invisible to every resistance-mutation screen, Lineage switch in KMT2A-rearranged leukemia — the same clone changes what kind of blood cell it is, The leukaemia that changed lineage in eleven days and changed back when the drug stopped: KMT2A::AFF4 infant ALL on blinatumomab
137. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30487223
     Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.

     Li JF, Dai YT, Lilljebjorn H, Shen SH, Cui BW, Bai L, et al. · Proc Natl Acad Sci U S A 2018
     used by Four sources give ZNF384 three different zinc-finger counts - 8, 6 and 'five to eight' - and the paralogue's feature table explains where the 6 comes from, How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, ZNF362 - the paralogue that makes the same leukaemia with the same partners, and that explains the six-zinc-finger convention
138. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29870403
     Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer.

     Yang Z, Shah K, Busby T, et al. · J Clin Invest 2018
     used by Four ways a WDR5 result can be true and have nothing to do with KMT2A
139. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29507226
     Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells

     Patzelt T, Keppler SJ, Gorka O, Thoene S, Wartewig T, Reth M, et al. · Proc Natl Acad Sci U S A 2018
     used by FOXP1 - the forkhead repressor that licenses the pro-B to pre-B transition and blocks apoptosis with NF-kB, sitting at a 105x MLL1-N bin in a leukaemia whose defining lesion is a pro-B arrest
140. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29590629
     Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia

     Maiques-Diaz A, Spencer GJ, Lynch JT, Ciceri F, Williams EL, Amaral FMR, Wiseman DH, Harris WJ, Li Y, Sahoo S, Hitchin JR, Mould DP, Fairweather EE, Waszkowycz B, Jordan AM, Smith DL, Somervaille TCP · Cell Reports 22:3641-3659 2018
     used by GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way, The LSD1–GFI1 SNAG interface — a second worked example of drugging an undruggable repressor through its partner
141. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.preprint
     Spatial chromosome folding and active transcription drive DNA fragility and formation of oncogenic MLL translocations - complete preprint full text with methods (179,145 characters), read 2026-09-22

     Gothe HJ, Bouwman BAM, Gusmao EG, Piccinno R, Sayols S, Drechsel O, Petrosino G, Minneker V, Josipovic N, Mizi A, Nielsen CF, Wagner EM, Takeda S, Sasanuma H, Hudson DF, Kindler T, Baranello L, Papantonis A, Crosetto N, Roukos V · bioRxiv (published as Mol Cell 75:267-283.e12, PMID 31202576) 2018
     used by Gothe 2019's deposit is all-human, has base-resolution break lists, includes primary CD34+ marrow and a transcription-inhibition arm - and contains no CTCF or cohesin perturbation of any kind, Gothe 2019's full text IS reachable - not through PMC, which has no deposit, but through an author search that surfaces the bioRxiv preprint; fourteen routes, and the two Europe PMC id links that look like a PMC record are both traps, Not one of the four studies in this dispute measured CTCF or cohesin occupancy in a human blood cell - so this beat read ENCODE instead, and the element is a STRONGER CTCF site in a B-lymphoblastoid line than in HCT116, with the summit at the same base, Premise (iii) was not falsified at this locus - Gothe 2019 measures MLL breakage and MLL-AF4 fusion in the same cells and they move TOGETHER under TDP2 loss; what TDP2 actually falsifies is a premise about break FORMATION that the triad never stated, The cohesin-degron break map was run in the one human cell line where the KMT2A element does not break - so premise (i) is not underpowered, it is unaddressed
142. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29882329
     GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.

     Hengel H, Keimer R, Deigendesch W, et al., Schols L · Clin Genet 2018
     used by GPT2 (Q8TD30) - the EARLIEST-moving and third-most menin-selective gene in the serine arm, and the one REH cannot control because it is below the array floor there
143. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 29721197
     Backtracked analysis of preleukemic fusion genes and DNA repair foci in umbilical cord blood of children with acute leukemia.

     Škorvaga M, Durdík M, Košík P, Marková E, Holop M, Kubeš M, et al. · Oncotarget 2018
     used by H2AX - filed as a gene and not as a mark, and the reason that decision changes what the graph can say, TP53BP1 (53BP1) - the end-protection factor that decides between the two repair routes, reachable only under the wrong symbol
144. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28540746
     KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia.

     Xu X; Nagel S; Quentmeier H; Wang Z; Rosenwald A; Meyer C; Drexler HG; MacLeod RAF · Leuk Lymphoma 2018
     used by H3K9me1 - the only H3K9 state whose level at the KMT2A breakpoint cluster region has ever been measured, and it is LOW there until KDM3B is removed, H3K9me2 - named sixty times in this graph with no entry of its own, the mark that defines the lamina-associated domains the fusion's targets sit beside, and the only H3K9 methylation state ever measured at a KMT2A fusion's own binding sites, KDM3B - the H3K9me1/2 demethylase that sits on the KMT2A breakpoint cluster region and keeps it from rearranging, and the only leukaemia gene in this graph whose direction of effect flips between the myeloid and the lymphoid literature
145. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30013077
     Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment.

     Huang X, Guo B, Liu S, Wan J, Broxmeyer HE · Nat Commun 2018
     used by HDAC5 - the eraser in an existing entry's own id, and the one HDAC in this graph that erases a mark on a fusion partner protein rather than on a histone
146. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29978456
     Paediatric patients with acute leukaemia and KMT2A (MLL) rearrangement show a distinctive expression pattern of histone deacetylases.

     Vega-Garcia N, Malatesta R, Estella C, Perez-Jaume S, Esperanza-Cebollada E, Torrebadell M, et al. · British Journal of Haematology 182(4):542-553 2018
     used by HDAC9 - the only HDAC with a KMT2A-rearrangement expression signature across 211 paediatric patients, and it is high, prognostic, and independent of partner and lineage, No HDAC-inhibitor result in this disease attributes to an HDAC enzyme - the only per-enzyme evidence is genetic, and it says the enzyme is not fusion-specific, The HDAC7 direction conflict is scaffold versus catalysis: removing the protein and blocking its catalysis are opposite interventions, because class IIa HDACs barely have any catalysis
147. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30145929
     Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.

     Maurer MS, Schwartz JH, Gundapaneni B, et al. · New England Journal of Medicine 2018
     used by Hypothesis — forced-oligomerisation interfaces are the mutation-resistant drug targets the fusion field has been ignoring
148. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28626219
     Base excision repair proteins couple activation-induced cytidine deaminase and endonuclease G during replication stress-induced MLL destabilization

     Gole B, Mian E, Rall M, Wiesmuller L · Leukemia 2018
     used by Hypothesis: the KMT2A break can be prevented rather than the fusion treated - stated so it can be killed, and it probably should be, Programmed DNA breaks - V(D)J and class switching - and the verdict on whether either one breaks KMT2A, Replication stress, AID, base-excision repair and endonuclease G cut the KMT2A locus, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
149. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29934777
     Targeted resequencing of a locus for heparin-induced thrombocytopenia on chromosome 5 identified in a genome-wide association study

     Witten A, Bolbrinker J, Barysenka A, Huber M, Ruhle F, Nowak-Gottl U, Garbe E, Kreutz R, Stoll M · Journal of Molecular Medicine (Berlin) 96(8):765-775 2018
     used by ICE1 — the 2,266-residue scaffold of the little elongation complex, the subunit that acts at initiation, and zero papers connecting it to leukaemia of any kind, Interactome round 4: what was counted, what was written, what was rejected, and the two alias traps this beat fell into and caught
150. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29860938
     Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.

     DiNardo CD, Stein EM, de Botton S, et al. · N Engl J Med 2018
     used by IDH1 - the same oncometabolite, the same assay, and NO enrichment in KMT2A-rearranged AML (6.7% vs 7.6%, p = 0.53): the control that makes the IDH2 result interpretable, Ivosidenib - the approved IDH1 inhibitor, recorded here so that nobody reaches for it: IDH1 is the paralogue that is NOT enriched in KMT2A-rearranged AML
151. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29476152
     Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation.

     Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL, Hu YC, Hüttelmaier S, Skibbe JR, Su R, Deng X, Dong L, Sun M, Li C, Nachtergaele S, Wang Y, Hu C, Ferchen K, Greis KD, Jiang X, Wei M, Qu L, Guan JL, He C, Yang J, Chen J · Nat Cell Biol 2018
     used by IGF2BP2 — the paralogue co-over-expressed with IGF2BP3 in MLL/AF4 B-ALL, and the one with an inhibitor in another leukaemia, IGF2BP3 — an RNA-binding protein required for MLL-Af4 leukaemogenesis in mice that CRISPR barely touches in human lines, IGF2BP3 works in cytoplasmic RNA granules - the only compartment in this beat where a drug is already pointed, and nobody has looked at it in a leukaemia cell
152. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29563185
     Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.

     Zhang H, Zhou B, Qin S, Xu J, Harding R, Tempel W, Nayak V, Li Y, Loppnau P, Dou Y, Min J · Genes Dev 2018
     used by Import class 3: the DOT1L-AF10 coiled-coil axis, an MLLT10 mechanism with no counterpart in the index fusion, MLLT10 (AF10): the discarded PZP reader — the one partner where loss is proven to be the oncogenic event, MLLT10 / AF10 — domain architecture and residue coordinates
153. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29174768
     Acetylation of TBX5 by KAT2B and KAT2A regulates heart and limb development.

     Ghosh TK, Aparicio-Sánchez JJ, Buxton S, Ketley A, Mohamed T, Rutland CS, Loughna S, Brook JD · J Mol Cell Cardiol 2018
     used by KAT2B / PCAF - named in an existing entry's own id and never written, and the only acetyltransferase in this graph whose substrate is a fusion partner protein
154. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28991411
     Structural insights into the nuclear import of the histone acetyltransferase males-absent-on-the-first by importin alpha1.

     Zheng W, Wang R, Liu X, Tian S, Yao B, Chen A, Jin S, Li Y · Traffic 2018
     used by KAT8/MOF is not only a chromatin enzyme: a measured mitochondrial pool binds mtDNA, and the chromatin address depends on which complex it is in
155. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29594337
     Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia.

     Li Y, Zhang M, Sheng M, et al. · J Cancer Res Clin Oncol 2018
     used by KDM6B (JMJD3) - UTX's paralogue, which this graph has argued about for cycles without writing
156. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 29477140
     AURKA Suppresses Leukemic THP-1 Cell Differentiation through Inhibition of the KDM6B Pathway.

     Park JW, Cho H, Oh H, Kim JY, Seo SB · Mol Cells 2018
     used by KDM6B (JMJD3) - UTX's paralogue, which this graph has argued about for cycles without writing
157. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30135578
     Structure of activated transcription complex Pol II-DSIF-PAF-SPT6

     Vos SM, Farnung L, Boehning M, Wigge C, Linden A, Urlaub H, Cramer P · Nature 560(7720):607-612 2018
     used by KMT2A-rearranged cells need the factors retained through elongation MORE and the factors ejected at pause release LESS — a six-gene asymmetry nobody has reported, NELF — the brake that has to come off for elongation, absent from the KMT2A literature, and less required in KMT2A-rearranged lines than in any other leukaemia, NELFB (COBRA1) — the NELF scaffold, and the single least KMT2A-selective gene of the sixty least selective in the genome, SUPT4H1 (SPT4) — zero papers linking it to KMT2A, and the 138th most KMT2A-selective gene out of 17,728, SUPT5H (SPT5) — the pausing factor the KMT2A field has never studied, and the counted absence that undercuts 'the fusion hijacks pause release', The ELL/EAF activation module (ELL2, EAF1, EAF2) — a general elongation stimulator, not a KMT2A-fusion dependency
158. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30021884
     Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

     Fasci D, van Ingen H, Scheltema RA, Heck AJR · Molecular & cellular proteomics : MCP 2018
     used by KMT2A-TMCO1 is a single DSSO crosslink in one detergent fraction of isolated U2OS nuclei with no bait on either side; TMCO1 is an ER-membrane calcium channel and the source paper attributes 4% of its links to nucleus-ER contamination - declined, PSIP1-GDF5 is a single DSSO crosslink in isolated U2OS nuclei with no bait on either side; GDF5 is a secreted cartilage growth factor, and the source paper itself attributes 30% of its cross-compartment links to contamination during nuclei isolation - declined, PSIP1-IGHMBP2 is a single DSSO crosslink in one detergent fraction of U2OS nuclei with no bait; unlike the other Fasci rows the compartments match, so this is declined on evidence depth alone - and IGHMBP2 is a fourth ribosome-biogenesis-adjacent protein on this list, PSIP1-PPP1R13B (ASPP1) is a single DSSO crosslink in unfractionated U2OS nuclei with no bait; both proteins are nuclear and both are stress-response regulators, so this is declined on evidence depth alone and is the most biologically coherent row in the beat, PSIP1-TMEM214 is a DSSO crosslink in two preparations of isolated U2OS nuclei with no bait on either side; TMEM214 is an ER-membrane mediator of CASP4-dependent ER-stress apoptosis - declined
159. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 29384595
     MLL-rearranged acute myeloid leukemia: Influence of the genetic partner in allo-HSCT response and prognostic factor of MLL 3' region mRNA expression.

     Burillo-Sanz S, Morales-Camacho RM, Caballero-Velazquez T, et al. · European Journal of Haematology 2018
     used by KMT2A::MLLT1 outcome by age band: favourable in adult ALL, high-risk in childhood AML, and completely unstratified in the infants who are most of the disease
160. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29326822
     Acute myeloid leukemia with KMT2A-SEPT5 translocation: A case report and review of the literature.

     Elzamly S, Chavali S, Tonk V, et al. · SAGE Open Med Case Rep 2018
     used by KMT2A::SEPTIN5 (MLL-SEPT5 / MLL-hCDCrel-1), t(11;22)(q23;q11.2)
161. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30455225
     A case of KMT2A-SEPT9 fusion-associated acute megakaryoblastic leukemia.

     Forlenza CJ, Zhang Y, Yao J, et al. · Cold Spring Harb Mol Case Stud 2018
     used by KMT2A::SEPTIN9 (MLL-SEPT9 / MLL-MSF), t(11;17)(q23;q25)
162. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB 6EMQ: Solution structure of the LEDGF/p75 IBD - MLL1 (aa 111-160) complex

     Sharma S, Cermakova K, De Rijck J, et al. · RCSB Protein Data Bank 2018
     used by LEDGF IBD to KMT2A: TWO motifs, not one - IBM1 at 124-133 and IBM2 at 147-152, and the Kd this graph recorded as missing is 14.7 uM
163. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30887005
     Leukemia Cutis in Childhood Acute Myeloid Leukemia: Epidemiological, Clinical, Biological, and Prognostic Characteristics of Patients Included in the ELAM02 Study

     Gouache E, Greze V, Strullu M, et al. · HemaSphere 2018
     used by Leukaemia cutis: the skin nodules that can be the first sign of infant leukaemia
164. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29797659
     Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia.

     Oberley MJ, Gaynon PS, Bhojwani D, Pulsipher MA, Gardner RA, Hiemenz MC, Ji J, Han J, O'Gorman MRG, Wayne AS · Pediatr Blood Cancer 2018
     used by Lineage switch to myeloid leukaemia under CD19-directed therapy in ZNF384-rearranged ALL - and in the one cohort that caught both families, the ZNF384 switch looked mutationally NOTHING like the KMT2A ones
165. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30209392
     The genetic basis and cell of origin of mixed phenotype acute leukaemia.

     Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, et al., Mullighan CG · Nature 2018
     used by Lineage switch to myeloid leukaemia under CD19-directed therapy in ZNF384-rearranged ALL - and in the one cohort that caught both families, the ZNF384 switch looked mutationally NOTHING like the KMT2A ones, Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act, The ZNF384-fusion immunophenotype - weak CD10 with aberrant CD13/CD33 - and the one marker that separates it from KMT2A-rearranged disease runs the OPPOSITE way to expectation, ZNF384 fusions make lineage-ambiguous leukaemia by acting in a haematopoietic stem cell - and the founding lesion is in the HSC itself, unlike Ph-like B-ALL
166. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29568061
     An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.

     Liu X, Salokas K, Tamene F, et al. · Nat Commun 2018
     used by LMNA - LEDGF is a prey of the nuclear-envelope MARKER bait, so this row is a statement about address, not about complex membership
167. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 29275929
     Endometrial stromal sarcomas and related neoplasms: new developments and diagnostic considerations.

     Hoang L, Chiang S, Lee CH · Pathology 2018
     used by Low-grade endometrial stromal sarcoma is a family of NuA4-acetyltransferase-to-Polycomb fusions, and that is why one of MBTD1's two fusions looks nothing like the other, MBTD1::EZHIP (MBTD1-CXorf67), t(X;17)(p11.2;q21.33) - MBTD1's other fusion, in which a NuA4 subunit delivers an H3K27M-mimicking PRC2 poison to low-grade endometrial stromal sarcoma
168. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29903765
     The fetal liver lymphoid-primed multipotent progenitor provides the prerequisites for the initiation of t(4;11) infant leukemia

     Malouf C, Ottersbach K · Haematologica 2018
     used by Lymphoid-primed multipotent progenitor (LMPP) — the bi-potent cell that explains how one fusion makes two lineages
169. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30244834
     The Mcm2-Ctf4-Polalpha Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands.

     Gan H, Serra-Cardona A, Hua X, Zhou H, Labib K, et al. · Mol Cell 2018
     used by MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7
170. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29394375
     Replication stress induces accumulation of FANCD2 at central region of large fragile genes.

     Okamoto Y, Iwasaki WM, et al. · Nucleic Acids Res 2018
     used by Measure replication stress directly in KMT2A-rearranged cells instead of inferring it from a dependency ranking, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
171. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29339748
     Dot1 regulates nucleosome dynamics by its inherent histone chaperone activity in yeast.

     Lee S, Oh S, Jeong K, et al. · Nature Communications 2018
     used by Measure the clearance clock directly: SNAP-tag H3.3 pulse-chase at KMT2A::AFF1 target genes, with and without DOT1L inhibition, in cycling and arrested cells, The clearance clock has machinery, and the machinery says the clock does NOT stop in a non-dividing cell - a postmitotic heart replaces its histones with a half-life of about two weeks, With no eraser, how fast the histone itself is replaced decides how much H3K79 methylation there is - and that sets the clock a DOT1L drug has to beat
172. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29526696
     LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia.

     Tarumoto Y, Lu B, Somerville TDD, et al. · Mol Cell 2018
     used by MEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of
173. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 29784935
     A causal mechanism for childhood acute lymphoblastic leukaemia

     Greaves M · Nature Reviews Cancer 2018
     used by Mel Greaves (Centre for Evolution and Cancer, ICR London) — natural history, in-utero origin and the prevention question
174. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29335487
     Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 /PET.

     Monazzam A, Lau J, Velikyan I, Li SC, Razmara M, Rosenstrom U, et al. · Scientific Reports 2018
     used by Menin represses GLP1R - the receptor a whole class of diabetes drugs exists to switch on
175. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29290617
     METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification

     Weng H, et al. · Cell Stem Cell 2018
     used by METTL14 — the other half of the m6A writer, with a real AML mechanism and zero KMT2A-specific records
176. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29348140
     Interactions, localization, and phosphorylation of the m6A generating METTL3-METTL14-WTAP complex.

     Schöller E; Weichmann F; Treiber T; Ringle S; Treiber N; Flatley A; Feederle R; Bruckmann A; Meister G · RNA 2018
     used by METTL3 — the m6A writer with a clinical-grade inhibitor, an MLL-rearranged AML mechanism, and a B-lymphoid signal that goes the wrong way
177. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29720486
     International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia

     Hrusak O, de Haas V, Stancikova J, et al. · Blood 2018
     used by Mixed phenotype acute leukaemia (MPAL) and acute leukaemia of ambiguous lineage, Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act
178. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 29550836
     Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta-analysis

     Maruffi M, Sposto R, Oberley MJ, Kysh L, Orgel E · Leukemia 2018
     used by Mixed-phenotype acute leukemia and KMT2A rearrangement — plasticity caught in the act
179. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29945938
     Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

     Xiao P, Sandhow L, Heshmati Y, Kondo M, Bouderlique T, Dolinska M, et al. · Blood Advances 2018
     used by MLL-AF9 leukaemia destroys the nerves that run its own niche — a mechanism class this graph had nothing on
180. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 29806701
     Neonatal leukaemia

     Roberts I, Fordham NJ, Rao A, Bain BJ · British Journal of Haematology 2018
     used by Monoblast — the immature monocyte that names FAB M5a, the dominant morphology of congenital KMT2A leukaemia, Plasmacytoid dendritic cell — the interferon cell that KMT2A-rearranged leukaemia occasionally becomes, and is more often mistaken for
181. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29133595
     Targeted Next-Generation Sequencing for Detecting MLL Gene Fusions in Leukemia.

     Afrin S, Zhang CRC, Meyer C, et al. · Mol Cancer Res 2018
     used by MRD by fusion transcript: fast, standardised, partner-limited - and structurally blind to KMT2A*, The second ring — smaller KMT2A-fusion mechanism labs, and where the literature actually points
182. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29489755
     Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours

     Ma X, Liu Y, Liu Y, Alexandrov LB, Edmonson MN, Gawad C, Zhou X, Li Y, Rusch MC, Easton J, Hermida LC, Davis S, Smith MA, Guidry Auvil JM, Gerhard DS, Zhang J, et al. · Nature 2018
     used by NCI TARGET — a finished paediatric leukaemia genomics resource, not an active partner, St. Jude Cloud and the Pediatric Cancer Genome Project — raw paediatric leukaemia genomes a small lab can get without a collaboration
183. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30135580
     Structure of paused transcription complex Pol II-DSIF-NELF

     Vos SM, Farnung L, Urlaub H, Cramer P · Nature 560(7720):601-606 2018
     used by NELF — the brake that has to come off for elongation, absent from the KMT2A literature, and less required in KMT2A-rearranged lines than in any other leukaemia, NELFB (COBRA1) — the NELF scaffold, and the single least KMT2A-selective gene of the sixty least selective in the genome, NELFE (RDBP) — the RNA-binding subunit of the pausing brake, and the alias that inflated a record count fifty-fold before it was caught, SUPT4H1 (SPT4) — zero papers linking it to KMT2A, and the 138th most KMT2A-selective gene out of 17,728, SUPT5H (SPT5) — the pausing factor the KMT2A field has never studied, and the counted absence that undercuts 'the fusion hijacks pause release'
184. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 29763382
     KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing.

     Kang JY, Kim JY, Kim KB, et al. · FASEB J 2018
     used by Nobody has convincingly found the H3K79 eraser - and that constraint sets the clock on every DOT1L inhibitor
185. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29943896
     Relatively favorable prognosis for MLL-rearranged childhood acute leukemia with reciprocal translocations.

     Yang L, Ding L, Liang J, Chen J, et al. · Pediatr Blood Cancer 2018
     used by Nobody has ever stratified any KMT2A::MLLT1 outcome or drug-response analysis by reciprocal or spliced status - a measured absence, with the queries, The partner-matched control arm is not 241 versus 219 - it is 153 versus 101, and in that subset the two groups make an identical fusion protein
186. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28690313
     The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis.

     Garrido Castro P, van Roon EHJ, Pinhancos SS, Trentin L, Schneider P, Kerstjens M, Te Kronnie G, Heidenreich O, Pieters R, Stam RW · Leukemia 2018
     used by Nobody knows which way to push H2Bub in this disease, and the only available compound pushes it upward, Panobinostat - the HDAC inhibitor this graph has reasoned about for cycles without having an entry for, with strong KMT2A-rearranged xenograft activity and a terminated adult trial, Panobinostat lowers H2B ubiquitination in MLL-rearranged ALL by suppressing RNF20/RNF40/WAC — the only clinical-stage agent that reaches this axis, and its one ALL trial was stopped for lack of efficacy, RNF20 (BRE1A) — the H2B ubiquitin ligase that MLL-rearranged leukaemia needs, and that DepMap says every other cancer line needs just as much, RNF40 (BRE1B) — the obligate partner of RNF20, and the one of the pair with a documented link to differentiation and bivalency resolution, The panobinostat H2Bub result is SEM and KOPN8 against a REH comparator: three human lines, two KMT2A partners, one non-KMT2A control, WAC — the adaptor that hands RNF20/RNF40 to RNA polymerase II, and the only member of this axis whose knockdown alone killed MLL-rearranged ALL cells
187. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30205049
     Mutant NPM1 Maintains the Leukemic State through HOX Expression.

     Brunetti L, Gundry MC, Sorcini D, et al. · Cancer Cell 2018
     used by NPM1c and XPO1: one drug, one output, two incompatible mechanisms - is the mutant needed in the cytoplasm or on the chromatin?
188. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30154186
     Mapping 3D genome organization relative to nuclear compartments using TSA-Seq as a cytological ruler

     Chen Y, Zhang Y, Wang Y, Zhang L, Brinkman EK, Adam SA, Goldman R, van Steensel B, Ma J, Belmont AS · Journal of Cell Biology 2018
     used by Nuclear speckles — the compartment everyone assumes KMT2A::AFF1 uses, on evidence that skips AFF1 itself
189. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 30349365
     Knockdown of NUDT21 inhibits proliferation and promotes apoptosis of human K562 leukemia cells through ERK pathway.

     Zhang L, Zhang W · Cancer Manag Res 2018
     used by NUDT21 / CFIm25 (O43809) - the CFIm subunit that picks poly(A) sites, in the pan-MLL-fusion core, and a paraspeckle protein
190. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30257209
     Nut Directs p300-Dependent, Genome-Wide H4 Hyperacetylation in Male Germ Cells

     Shiota H, Barral S, Buchou T, et al. · Cell Reports 2018
     used by NUTM1 (NUT) - a testis-restricted, fully disordered protein that writes no mark and instead switches ON a writer, and the 3' partner of the KMT2A-wild-type infant B-ALL with the opposite prognosis
191. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.news
     Tax Reform Impacts the Research Tax Credit, Domestic Production Activities Deduction and Orphan Drug Credit

     BDO USA · BDO Insights 2018
     used by Orphan drug designation: what it actually gives a KMT2A programme, and what it bends
192. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 30246348
     Long noncoding RNA NEAT1 modulates cell proliferation and apoptosis by regulating miR-23a-3p/SMC1A in acute myeloid leukemia

     Zhao C, Wang S, Zhao Y, Du F, Wang W, Lv P, Qi L · Journal of Cellular Physiology 2018
     used by Paraspeckles and NEAT1 — no KMT2A evidence at all, but a fusion oncoprotein in another leukemia uses NEAT1 as a differentiation brake
193. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30297393
     Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches.

     Das P, Veazey KJ, Van HT, et al. · Proc Natl Acad Sci U S A 2018
     used by PAXIP1 (PTIP) - the subunit that tells an MLL3/4 complex apart from a menin complex, and the only one with a leukaemic-niche phenotype
194. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29599493
     RING tetramerization is required for nuclear body biogenesis and PML sumoylation

     Wang P, Benhenda S, Wu H, et al. · Nature Communications 2018
     used by PML — domain architecture and residue coordinates
195. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30514760
     Nuclear condensates of the Polycomb protein chromobox 2 (CBX2) assemble through phase separation

     Tatavosian R, Kent S, Brown K, Yao T, Duc HN, Huynh TN, Zhen CY, Ma B, Wang H, Ren X · Journal of Biological Chemistry 2018
     used by Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1
196. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29371181
     Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells.

     Shima H, Takamatsu-Ichihara E, Shino M, Yamagata K, Katsumoto T, Aikawa Y, Fujita S, Koseki H, Kitabayashi I · Blood 2018
     used by RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once
197. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 30280786
     The therapeutic efficacy of pediatric ALL patients with MLL gene rearrangement treated with CCLG-ALL2008 protocol

     Sun YN, ..., Hu SY · European Review for Medical and Pharmacological Sciences 2018
     used by Route 5 rescued 2 of 32, and 21 of the 30 failures returned HTTP 200 with no article - each publisher failing at a constant, recognisable length
198. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29474905
     A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.

     Hoshii T, Cifani P, Feng Z, Huang CH, Koche R, Chen CW, Delaney CD, Lowe SW, Kentsis A, Armstrong SA · Cell 2018
     used by SETD1A — a leukemia dependency whose enzyme activity turns out to be dispensable
199. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29916805
     The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice

     Schmidt K, Zhang Q, Tasdogan A, Petzold A, Dahl A, Arneth BM, Slany R, Fehling HJ, Kranz A, Stewart AF, Anastassiadis K · eLife 7:e27157 2018
     used by SETD1B - the COMPASS paralogue round 4 deferred for want of a leukaemia paper, which had already been published: its SET domain sets H3K4me3 breadth and MYC in MLL-rearranged AML
200. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29249820
     SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia.

     Bu J, Chen A, Yan X, He F, Dong Y, et al. · Leukemia 2018
     used by SETD2 (Q9BYW2) - the H3K36 trimethyltransferase that binds all seven MLL fusions, and the only one of them with a published KMT2A::AFF1 dependency test
201. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30288907
     Discovery of an MLLT1/3 YEATS Domain Chemical Probe.

     Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, Rogers CM, Smith P, Panagakou I, Diaz-Saez L, Felce SL, Gamble V, Gileadi C, Halidi N, Heidenreich D, Chaikuad A, Knapp S, Huber KVM, Farnie G, Heer J, Manevski N, Poda G, Al-Awar R, Dixon DJ, Brennan PE, Fedorov O · Angew Chem Int Ed Engl 2018
     used by SGC-iMLLT - the MLLT1/MLLT3 YEATS chemical probe, and the 2026 paper that put it into KMT2A::AFF1 in vivo with a healthy-HSPC comparison
202. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29483235
     SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia.

     Chatterjee SS, Biswas M, Boila LD, Banerjee D, et al. · Mol Cancer Res 2018
     used by SMARCB1 (BAF47/INI1/SNF5) - zero entries, zero mentions and, on the evidence, correctly so: it is lost in primary AML rather than required, SMARCD2 (BAF60B) - named in one KMT2A paper in the whole of PubMed, and the dependency it carries is myeloid identity, not the rearrangement, SWI/SNF enumeration for KMT2A-rearranged leukaemia: every subunit searched, every count dated, and what was read and rejected
203. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29408457
     The pathogenic role of MEF2D-SS18 fusion gene in B-cell acute lymphoblastic leukemia.

     Zhang M, Mao D, Zhang W · Biochem Biophys Res Commun 2018
     used by SS18 - a SWI/SNF subunit that is itself a fusion partner in another cancer, and a lineage-independent dependency in KMT2A-rearranged lines
204. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30266814
     Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation

     Gachet S, et al. · Cancer Discov 2018
     used by SYNCRIP (hnRNP Q) — required for MLL leukaemia stem cells in one paper and a tumour suppressor deleted in T-ALL in another
205. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29650777
     MLL leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing.

     Schneidawind C, Jeong J, Schneidawind D, et al. · Blood Adv 2018
     used by t(9;11): the reciprocal product is made, is engineered into every genome-editing model, and has never been separately tested
206. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30150451
     An Adult Patient with Early Pre-B Acute Lymphoblastic Leukemia with t(12;17)(p13;q21)/ZNF384-TAF15.

     Georgakopoulos N, Diamantopoulos P, Micci F, Giannakopoulou N, Zervakis K, Dimitrakopoulou A, Viniou NA · In Vivo 2018
     used by TAF15::ZNF384 - the FET-partner version, where the naming order in the literature is a trap and the founding experiment says the transactivation domain is not doing the work, The ZNF384-fusion immunophenotype - weak CD10 with aberrant CD13/CD33 - and the one marker that separates it from KMT2A-rearranged disease runs the OPPOSITE way to expectation
207. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29438979
     Mitochondrial tyrosyl-DNA phosphodiesterase 2 and its TDP2S short isoform.

     Huang SN, Dalla Rosa I, Michaels SA, Tulumello DV, Agama K, Khiati S, et al. · EMBO Rep 2018
     used by TDP2 - the protein-adduct remover named in this graph's own mechanism entry and until now having no entry of its own
208. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30352306
     Specificity of MLL1 and TET3 CXXC domains towards naturally occurring cytosine modifications.

     Stroynowska-Czerwinska A, Piasecka A, et al. · Biochim Biophys Acta Gene Regul Mech 2018
     used by TET3 - the CXXC reader whose domain prefers 5-carboxylcytosine, and the only CXXC-family gene ever found mutated in a KMT2A-rearranged cohort, The human CXXC/CpG-reading family is exactly twelve proteins, and TET2 is not one of them
209. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     PXD009338 - Protein Interactions of 7 MLL-fusion Proteins (sample-processing and data-processing protocols)

     Skucha A, et al., deposited via PRIDE 2018-04-23, public 2018-05-25 · ProteomeXchange / PRIDE, EMBL-EBI 2018
     used by The 110 MLL-AF4-specific preys are 14.5% mitochondrial and 34% nuclear; the 42 pan-fusion preys are 2.4% mitochondrial and 88% nuclear — Fisher p = 0.042 on a nuclear-extract pulldown
210. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29217648
     The interaction of ENL with PAF1 mitigates polycomb silencing and facilitates murine leukemogenesis.

     Hetzner K, Garcia-Cuellar MP, Buttner C, et al. · Blood 2018
     used by The ENL YEATS acetyl-reader inside KMT2A::MLLT1: what it reads, what it does, and why both control arms carry it
211. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30082790
     Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit.

     Ray-Gallet D, Ricketts MD, Sato Y, et al. · Nature Communications 2018
     used by The HUCA complex (HIRA/UBN1/CABIN1/ASF1a) - four proteins, one job: put H3.3 into chromatin without waiting for S phase
212. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     The HDAC inhibitor Panobinostat (LBH589) exerts in vivo anti-leukaemic activity against infant MLL-rearranged acute lymphoblastic leukaemia (GSE78234)

     GEO submitters · NCBI Gene Expression Omnibus 2018
     used by The panobinostat H2Bub result is SEM and KOPN8 against a REH comparator: three human lines, two KMT2A partners, one non-KMT2A control
213. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30373828
     The in silico human surfaceome.

     · Proc Natl Acad Sci U S A 2018
     used by The screen this beat was dispatched to run 'because it has never been run' was published in Haematologica in 2022, used the same instrument, and is cited in this graph already - in an entry filed under innate immunity
214. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30217220
     Alternative splicing links histone modifications to stem cell fate decision.

     Xu Y, Zhao W, et al. · Genome Biol 2018
     used by The third job: LEDGF sits on transcribed gene bodies with splicing factors and changes exon choice in half the genes that have alternative isoforms
215. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 30203048
     Dot1 promotes H2B ubiquitination by a methyltransferase-independent mechanism.

     van Welsem T, Korthout T, Ekkebus R, Morais D, Molenaar TM, van Harten K, Poramba-Liyanage DW, Sun SM, Lenstra TL, Srivas R, Ideker T, Holstege FCP, van Attikum H, El Oualid F, Ovaa H, van Leeuwen F · Nucleic Acids Res 2018
     used by The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
216. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29992232
     Three classes of response elements for human PRC2 and MLL1/2-Trithorax complexes.

     Du J, Kirk B, Zeng J, Ma J, Wang Q, et al. · Nucleic Acids Res 2018
     used by Trithorax against Polycomb at HOXA: the textbook antagonism, and the two ways this disease breaks it
217. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 30431433
     Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma.

     Brien GL, Remillard D, Shi J, Hemming ML, et al. · Elife 2018
     used by Two published ways a fusion oncoprotein engages BAF - be a subunit, or recruit it with a disordered domain - and KMT2A has never been tested for either
218. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 30285846
     UBN1/2 of HIRA complex is responsible for recognition and deposition of H3.3 at cis-regulatory elements of genes in mouse ES cells.

     Xiong C, Wen Z, Yu J, et al. · BMC Biology 2018
     used by UBN1 - the subunit that decides the HIRA complex is carrying H3.3 and not H3.1, by reading a single glycine
219. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29208711
     Molecular basis for the recognition of the human AAUAAA polyadenylation signal.

     Sun Y, Zhang Y, Hamilton K, Manley JL, Shi Y, Walz T, Tong L · Proc Natl Acad Sci U S A 2018
     used by WDR33 (Q9C0J8) - the subunit that reads AAUAAA, in the pan-MLL-fusion core, and the plant homolog of which physically links 3' processing to H3K4 demethylation
220. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29735299
     Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial.

     Saussele S, Richter J, Guilhot J, et al. · The Lancet Oncology 2018
     used by Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
221. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 29192213
     Differentiation therapy revisited

     de The H · Nature Reviews Cancer 2018
     used by Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it
222. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29298432
     Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions.

     Winczura K, Schmid M, Iasillo C, Molloy KR, Harder LM, Andersen JS, LaCava J, Jensen TH · Cell Rep 2018
     used by ZC3H18 (Q86VM9) - the CBC-to-exosome bridge in the pan-MLL-fusion core, and the ONLY member of this tranche whose own complex came with it
223. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29911449
     Expression of a novel ZMYND11/MBTD1 fusion transcript in CD7(+)CD56(+) acute myeloid leukemia with t(10;17)(p15;q21)

     Yamamoto K, Yakushijin K, Ichikawa H, et al. · Leukemia & Lymphoma 2018
     used by ZMYND11::MBTD1, t(10;17)(p15;q21) - a chromatin reader welded to the NuA4/TIP60 acetyltransferase, maintaining Hoxa/Meis1/Myb/Myc/Sox4 in AML: the KMT2A-fusion architecture built from different parts
224. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28978671
     Transcriptional memory of cells of origin overrides beta-catenin requirement of MLL cancer stem cells.

     Siriboonpiputtana T, Zeisig BB, Zarowiecki M, Fung TK, Mallardo M, Tsai CT, et al. · EMBO J 2017
     used by 'Transcriptional memory' means two different things in this literature, and both of them are used about MLL leukaemia, PRMT1 — an MLL-fusion cofactor whose first-in-human inhibitor was terminated for lack of efficacy and toxicity
225. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28076791
     MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia.

     Kerry J, Godfrey L, Repapi E, et al. · Cell Rep 2017
     used by 2-hydroxyglutarate competitively inhibits the alpha-KG dioxygenases - and it hits the TET demethylases AND the KDM histone demethylases, which is why its net effect on a CXXC reader is not predictable, A caveat that weakened the index fusion, wrongly: the MLL-AF4 spreading deposition is 30 SEM samples plus six other lines, all human, An unstated system is not a coin flip: four out of five resolve away from the index disease, so silence in this graph is systematically optimistic, Anti-AFF1 antibodies: attributable on a gel, not attributable in a microscope, and the classic localisation result shows exactly why, Attribution audit 5 of 5 - where KMT2A::AFF1 sits on chromatin: the field's standard attribution heuristic is invalidated by the paper that founded it, but two real survivors exist, Bounded absence: every chromatin measurement under a menin inhibitor is in an adult-derived line, and none is in an infant KMT2A::AFF1 model, CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, Enhancer usage in KMT2A-rearranged leukemia — occupancy and amplification, not hijacking, and not super-enhancers, Enhancer-promoter contacts at KMT2A-fusion target loci — what the fusion uses, what it does not, and what survives the drug, Experiment: is the primed state in KMT2A::AFF1 actually bivalent? Multi-mark CUT&Tag on primary infant blasts, Experiment: put the resistant and the sensitive fusion side by side - if a MEN1 interface mutant keeps the fusion in place while the wild type moves it, relocation is real and menin is what chooses the address, H3K36me2/3 - the mark that physically switches PRC2 off, that LEDGF reads to reach chromatin, and that a comparator fusion uses to keep EZH2 off HOXA, How much of this graph's mechanism is somebody else's fusion? A counted answer: 54% of fusion-bearing evidence, and 0% from a dedicated human KMT2A::AFF1 experiment, Hypothesis: KMT2A::AFF1 rewires splicing, because AFF1's own protein family are G-quadruplex RNA-binding splicing modulators and the fusion keeps AFF1, Hypothesis: LEDGF licenses elongation at fusion target genes rather than anchoring the fusion, which predicts that a LEDGF agent is epistatic with BET and CDK9 inhibition and invisible in a fusion-ChIP assay, Hypothesis: menin inhibition does not clear the fusion from chromatin but redistributes it onto the four fifths of the unmethylated CpG address it normally ignores, Hypothesis: the menin inhibitor's effect is inactivation in place, not eviction - the fusion keeps most of its sites and loses its output, Hypothesis: the R-loop landscape of a KMT2A::AFF1 blast is remodelled by the fusion and is both a vulnerability and a source of ongoing genome instability, IDH2 - the hypermethylating co-mutation that IS enriched in KMT2A-rearranged AML (16.0% vs 10.4%), at p = 0.0004 and not the p < 0.0001 the abstract claims, If the fusion's address requires unmethylated CpG, a hypermethylating co-mutation should be selected AGAINST - and IDH2 is selected FOR, which means the address is not the limiting resource, In KMT2A::AFF1 there is no oncogenic DOT1L unit: all H3K79 methylation is the endogenous MLLT10-directed activity, working on genes the fusion has opened, Kerry 2017's 'sufficient but not necessary' is a figure title with no experiment behind the second half - and the paper's own knockdowns run the other way, KMT2A::AFF1 has no mapped interface to DOT1L: it lacks both structurally defined recruitment modules, and the one complex-level route claimed for it is contested by reconstitution, Knock a tag-plus-degron cassette into the endogenous KMT2A::AFF1 allele in SEM - one construct that makes five claim classes attributable, LEDGF does NOT hold the fusion on chromatin: knocking it down INCREASES fusion occupancy, and an IBD-binding-dead fusion still binds its targets, Only a handful of loci lose fusion occupancy under a menin inhibitor, and they are the same few whether menin is drugged or deleted: MEIS1, MEF2C, JMJD1C - not HOXA, not MYB, Put mutant IDH2 into SEM and ask three questions at once: does the unmethylated-CpG pool shrink, does the fusion move, and does its competitor move, Re-founding the address argument: the CXXC domain cannot specify a location at any affinity, and a tighter one would be worse, Step 1 — How the fusion finds its genes: AT-hooks and the CXXC domain reading unmethylated CpG, Step 4 — The histone mark: DOT1L and H3K79me2/3 at fusion target genes (and why global expression barely moves), The CXXC-DNA affinity is a ten-point ladder from 44 uM to 33 nM, not two numbers 1,300-fold apart, and every step but the last is under 5.5-fold, The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The gain question is answerable today for free: GSE127508 contains MLL1n ChIP-seq in a fusion-only line, plus and minus VTP-50469, and nobody has called peaks on the treated sample, The imports that were never necessary: H3K79 methylation in KMT2A::AFF1 has its own literature, and this graph barely cites it, The measurement everybody said was missing exists: in SEM cells KMT2A::AFF1 occupies 20% of unmethylated CpG sites, CXXC1 50% and KDM2B 89%, and only the fusion tracks menin (r2 = 0.96), The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here, What could refute the menin-interface bet, restated after the provenance audit: three tests, none of which is about menin binding
226. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia (GSE83671)

     GEO submitters · NCBI Gene Expression Omnibus 2017
     used by A caveat that weakened the index fusion, wrongly: the MLL-AF4 spreading deposition is 30 SEM samples plus six other lines, all human, An unstated system is not a coin flip: four out of five resolve away from the index disease, so silence in this graph is systematically optimistic
227. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27840424
     Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia.

     Dafflon C, Craig VJ, Mereau H, Grasel J, Schacher Engstler B, Hoffman G, et al. · Leukemia 2017
     used by A menin inhibitor does not only take something away - it causes PRC1.1 to put something on, and the drug needs the cell's own silencing machinery to work, Experiment: time-to-resistance, not synergy index, as the readout for menin-inhibitor combinations, H3K79 methylation is what keeps Polycomb off - and that, not gene silencing, is what a DOT1L inhibitor actually undoes, Hypothesis: only a mechanistically orthogonal partner pre-empts menin-inhibitor resistance; a second chromatin agent will not, Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field, SUPERSEDED IN PART, CYCLE 56 - the MI-2-2 response is ~9x fusion-selective (that stands), but 'does not touch HOXA or MEIS1' was a fact about a weak compound: VTP-50469 collapses MEIS1 -5.25 log2 in the same line, When MYC falls after a menin inhibitor, there are three mechanisms it could be, and no published experiment separates them
228. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28079019
     An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites

     Skene PJ, Henikoff S · eLife 2017
     used by A promoter window is not a gene: what it means to say a protein 'sits on gene X's switch', Tile chr5:2,750,677-2,752,892 at 100 bp from the GSE252378 bigWigs and ask which TSS the p454 signal sits on, When a 2 kb promoter call fires at a window shared with another gene, the neighbour fires too 91.3% of the time - against 4.3% for random promoter pairs
229. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27443263
     Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of romidepsin.

     Cruickshank MN, Ford J, Cheung LC, Heng J, Singh S, Wells J, et al. · Leukemia 31(1):40-50 2017
     used by Acetylation is a cycle, not a mark - and this graph holds one complete cycle, on a residue the fusion throws away, PER-490 (CVCL_W986) — a KMT2A::AFF1 B-ALL line from a nine-day-old infant, Romidepsin - the HDAC inhibitor with the best preclinical case in KMT2A-rearranged INFANT ALL specifically, and a mechanism that is not about histones at all
230. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28794467
     TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription.

     Gomez-Herreros F, Zagnoli-Vieira G, Ntai I, Martinez-Macias MI, Anderson RM, Herrero-Ruiz A, Caldecott KW · Nature Communications 2017
     used by Adjudicated: CTCF does not do opposite things at KMT2A - it does one thing, and this graph's contradiction is an untested premise about whether a break becomes a rearrangement, Analysis (runnable): mine the KMT2A junction sequences for repair-pathway signature, and count the one junction class with a genetic control behind it, Break formation, break persistence and break fate are three quantities, and every assay in this dispute reports the middle one - which is why the triad's third premise is ambiguous rather than weak, CTCF/cohesin occupancy at the KMT2A exon-11 anchor is both the cause of the break and the chaperone of its correct repair - so losing it gives FEWER breaks and MORE rearrangements, Experiment: bait the KMT2A breakpoint cluster region and sequence everything it joins to, in a fetal-like human progenitor, Hypothesis: the KMT2A break can be prevented rather than the fusion treated - stated so it can be killed, and it probably should be, Premise (iii) was not falsified at this locus - Gothe 2019 measures MLL breakage and MLL-AF4 fusion in the same cells and they move TOGETHER under TDP2 loss; what TDP2 actually falsifies is a premise about break FORMATION that the triad never stated, TDP2 - the protein-adduct remover named in this graph's own mechanism entry and until now having no entry of its own, TDP2 unglues trapped topoisomerase II from the KMT2A locus - it suppresses translocations overall and manufactures one rare junction class, The measurement that settles the CTCF dispute: degron-grade CTCF removal versus cohesin removal, with DNA breaks AND rearrangement outcome read out at the same 1 kb of KMT2A in the same cells, reported as rearrangements per break
231. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28844694
     Cancer-specific retargeting of BAF complexes by a prion-like domain

     Boulay G, Sandoval GJ, Riggi N, et al. · Cell 2017
     used by Analysis (planned) — comparative druggability scan of every obligate fusion-partner interface in the atlas, EWSR1 — domain architecture and residue coordinates, EWSR1::FLI1 — the comparator that shows condensate formation has an optimum, and that forcing a fusion into the nucleolus switches it off, EWSR1::FLI1 (EWS-FLI1), t(11;22)(q24;q12), Experiment (proposed) — cross-family interface point-mutant panel: is the obligate interface real in each fusion?, FLI1 — domain architecture and residue coordinates, Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion, Mechanism class 4 — condensate-driven transcriptional rewiring (NUP98-r, EWSR1::FLI1), SS18 - a SWI/SNF subunit that is itself a fusion partner in another cancer, and a lineage-independent dependency in KMT2A-rearranged lines, Two published ways a fusion oncoprotein engages BAF - be a subunit, or recruit it with a disordered domain - and KMT2A has never been tested for either
232. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28735753
     Genome Organization Drives Chromosome Fragility

     Canela A, Maman Y, Jung S, et al. · Cell 2017
     used by Analysis (runnable): is anything actually enriched at KMT2A breakpoints? The test has never been run against a background that could say no, Chromatin loop anchors are DNA-break hotspots - and the two papers that established it disagree about why, CTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients, Hypothesis: KMT2A and AFF1 break where they do because both breakpoint regions are CTCF/cohesin loop anchors sitting in the same nuclear hub, Move the cohesin degron into a cell where the element actually breaks: RAD21-AID in Nalm6 or CD34+, sBLISS plus both END-seq variants, with the fusion readout in the same cells, Run in coordinates: the protective CTCF site and the patient break-prone window are ONE element, it is cohesin-bound, and the 'functional cut point' is 3.75 kb away - two of the graph's three exon-11s were the same exon and the third was not, TOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically, What the CTCF-protects paper actually cites: it names Gothe and Atkin in ONE direction-free sentence and declares the direction unresolved, and the two papers that ran the reciprocal experiment are absent from all 81 of its references
233. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28424353
     Constrained release of lamina-associated enhancers and genes from the nuclear envelope during T-cell activation facilitates their association in chromosome compartments

     Robson MI, de Las Heras JI, Czapiewski R, Sivakumar A, Kerr ARW, Schirmer EC · Genome Research 2017
     used by Analysis: does the fusion's target set sit at lamina-associated domain borders? A free overlay of published LAD maps on published fusion occupancy, The nuclear lamina and lamina-associated domains - evidence grade for KMT2A: weak and indirect, not none
234. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28967863
     Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers

     Kelso TWR, Porter DK, Amaral ML, Shokhirev MN, Benner C, Hargreaves DC · Elife 2017
     used by ARID1B (BAF250b) - the cBAF paralogue whose deletion PROMOTES MLL-AF9 leukaemogenesis, which makes it the one gene in this beat whose published KMT2A-fusion result points the wrong way for a drug target
235. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 28675638
     Azacitidine successfully maintained the second remission in an infant with KMT2A-rearranged acute lymphoblastic leukemia who relapsed after unrelated cord blood transplantation.

     Chijimatsu I, Imanaka Y, Tomizawa D, et al. · Pediatr Blood Cancer 2017
     used by Azacitidine - the one hypomethylating agent actually given to infants with KMT2A-rearranged ALL: safe, demonstrably demethylating, and it did not change survival
236. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27786413
     DNA methylation profiling of pediatric B-cell lymphoblastic leukemia with KMT2A rearrangement identifies hypomethylation at enhancer sites

     · Pediatric Blood & Cancer 2017
     used by BCL11A — the sickle-cell target whose binding sites lose methylation in this disease
237. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28273028
     Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia

     Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ · N Engl J Med 2017
     used by BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11), Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
238. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28560323
     CTCF facilitates DNA double-strand break repair by enhancing homologous recombination repair.

     Hilmi K, Jangal M, Marques M, Zhao T, Saad A, et al. · Science Advances 2017
     used by BRCA1 (P38398, 1,863 aa) - named in 19 entries of this graph and never written: the HR mediator that CTCF and the H3K9 machinery are now reported to license at a break, and the only cascade member with a human therapy-related-leukaemia signal after topoisomerase II therapy, The CTCF licensing cascade: CTCF recruits HP1-gamma, KAP1, SUV39H1, SETDB1 and KDM5A to a break, that repressive chromatin licenses EARLY BRCA1/BARD1, and early BRCA1/BARD1 licenses EXO1/DNA2 long-range resection - measured entirely in U2OS and HEK-293T, with engineered breaks and one etoposide arm
239. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29240787
     BRD3/4 inhibition and FLT3-ligand deprivation target pathways that are essential for the survival of human MLL-AF9+ leukemic cells.

     Carretta M, Brouwers-Vos AZ, Bosman M, Horton SJ, Martens JHA, Vellenga E, et al. · PLoS One 12(12):e0189102 2017
     used by BRD3 - named in the founding BET paper's own mechanism and in one title since, and not once separated from BRD4 by any experiment in this disease
240. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28653617
     Replication Study: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

     Shan X, Fung JJ, Kosaka A, Danet-Desnoyers G · eLife 6:e25306 2017
     used by BRD3 - named in the founding BET paper's own mechanism and in one title since, and not once separated from BRD4 by any experiment in this disease
241. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28710461
     Bromodomain factors of BET family are new essential actors of pericentric heterochromatin transcriptional activation in response to heat shock.

     Col E, Hoghoughi N, Dufour S, Penin J, Koskas S, Faure V, Ouzounova M, Hernandez-Vargash H, Reynoird N, Daujat S, Folco E, Vigneron M, Schneider R, Verdel A, Khochbin S, Herceg Z, Caron C, Vourc'h C · Sci Rep 2017
     used by BRD3 - named in the founding BET paper's own mechanism and in one title since, and not once separated from BRD4 by any experiment in this disease
242. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.trial_registry
     ClinicalTrials.gov record NCT01713582, A Phase I, Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/MK-8628 in Haematological Malignancies

     Oncoethix GmbH; Merck Sharp & Dohme · ClinicalTrials.gov 2017
     used by BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing
243. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     NCBI GEO SuperSeries GSE99197 and SubSeries GSE99194/99195/99196 - esummary db=gds records, supplementary filelist.txt for GSE99194 and GSE99197, and the full GSE99194 sample listing with per-sample !Sample_organism_ch1, retrieved 2026-09-22

     NCBI Gene Expression Omnibus · NCBI GEO 2017
     used by Canela 2017 deposited NO cohesin-depletion experiment - and it did deposit human END-seq in a B-cell-precursor leukaemia line, which nobody here had looked for
244. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     NCBI GEO sample GSM2635574 (targ=self, form=text, view=full) and GSE99194 supplementary filelist.txt, retrieved 2026-09-22

     NCBI Gene Expression Omnibus · NCBI GEO 2017
     used by Canela 2017 deposited NO cohesin-depletion experiment - and it did deposit human END-seq in a B-cell-precursor leukaemia line, which nobody here had looked for
245. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28130444
     Cell Cycle-independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection.

     Fan Y, Mok CK, Chan MC, Zhang Y, Nal B, Kien F, Bruzzone R, Sanyal S · J Biol Chem 2017
     used by CCND3 (cyclin D3) — the scan's rank-4 hit, and the only one of the four with a drug class already in children
246. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28262505
     Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

     Cheung KL, Zhang F, Jaganathan A, Sharma R, Zhang Q, Konuma T, Shen T, Lee JY, Ren C, Chen CH, Lu G, Olson MR, Zhang W, Kaplan MH, Littman DR, Walsh MJ, Xiong H, Zeng L, Zhou MM · Molecular Cell 65(6):1068-1080.e5 2017
     used by CCNT1 and CCNT2 have no histone substrate and reach chromatin on someone else's back: Brd4 recruits cyclin T1 and Cdk9 to acetylated chromatin and drives Pol II Ser2 phosphorylation - a borrowed address, which is a third annotation state the corpus has no word for
247. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27784674
     Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking.

     Braig F, Brandt A, Goebeler M, Tony HP, Kurze AK, Nollau P, Bumm T, Böttcher S, Bargou RC, Binder M · Blood 2017
     used by CD19 - the molecule this disease is treated by, named in 114 entries and written in none of them until now, The plasma membrane - the one compartment this graph targets with drugs and had never written down
248. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28131992
     The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion.

     Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, Oberlies NH, Pearce C, et al. · J Natl Cancer Inst 2017
     used by CD274 (PD-L1) - named in zero entries of this graph until now, a direct MLL1-H3K4me3 target gene in another tissue, and a cell-intrinsic dependency of MLL-AF9 leukaemia-initiating cells
249. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28747436
     The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool.

     Siddiqui SS, Springer SA, Verhagen A, Sundaramurthy V, Alisson-Silva F, Jiang W, Ghosh P, Varki A · J Biol Chem 2017
     used by CD33 (SIGLEC3) - the aberrant myeloid antigen on a B-lineage blast, and the one antibody-drug-conjugate target with a positive randomised result in KMT2A-rearranged disease, One trial, two published analyses, never crossed: gemtuzumab clearly helps KMT2A-rearranged children, and a common CD33 genotype abolishes gemtuzumab benefit — nobody has asked whether it abolishes it in them
250. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28644774
     CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531.

     Lamba JK, Chauhan L, Shin M, Loken MR, Pollard JA, Wang YC, Ries RE, Aplenc R, Hirsch BA, Raimondi SC, Walter RB, Bernstein ID, Gamis AS, Alonzo TA, Meshinchi S · J Clin Oncol 2017
     used by CD33 (SIGLEC3) - the aberrant myeloid antigen on a B-lineage blast, and the one antibody-drug-conjugate target with a positive randomised result in KMT2A-rearranged disease
251. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 31966839
     Elevated nuclear CDK6 is associated with an unfavorable prognosis in lung adenocarcinoma patients.

     Li H, Zhang J, Xie Y · Int J Clin Exp Pathol 2017;10:9614-9620 2017
     used by CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true
252. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28410997
     International incidence of childhood cancer, 2001-10: a population-based registry study

     Steliarova-Foucher E, Colombet M, Ries LAG, et al. · Lancet Oncology 2017
     used by Childhood leukaemia worldwide, ages 0-14, How many infants worldwide, not just in the United States
253. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28732082
     Osteosarcoma enters a post genomic era with in silico opportunities: Generation of the High Dimensional Database for facilitating sarcoma biology research: A report from the Children's Oncology Group and the QuadW Foundation

     Glover J, Man TK, Barkauskas DA, Hall D, Tello T, Sullivan MB, Gorlick R, Janeway K, Grier H, Lau C, et al. · PLoS ONE 2017
     used by Children's Oncology Group — the trial network, the AALL protocol series and the biobank that no single lab can substitute
254. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28319093
     Human haematopoietic stem cell lineage commitment is a continuous process

     Velten L, Haas SF, Raffel S, Blaszkiewicz S, Islam S, Hennig BP, et al., Steinmetz LM · Nature Cell Biology 2017
     used by Common myeloid progenitor (CMP) — the fork at which KMT2A leukaemia almost always turns one way
255. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29137234
     The AF4-MLL fusion transiently augments multilineage hematopoietic engraftment but is not sufficient to initiate leukemia in cord blood CD34+ cells.

     Prieto C, Marschalek R, Kühn A, et al. · Oncotarget 2017
     used by Competing model 1: the reciprocal product starts the leukaemia and then leaves, KMT2A::AFF1 needs a developmental window and a lymphoid-committed cell — the cell type is a condition of transformation, not a consequence of it, SIAH1 — the E3 ligase that degrades AFF1, and that the reciprocal AF4::KMT2A fusion escapes, The reciprocal fusion (AFF1::KMT2A and friends): a second oncoprotein that opens chromatin for the first
256. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29180633
     Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer

     Zhang J, Cunningham JJ, Brown JS, Gatenby RA · Nature Communications 2017
     used by Competitive release and adaptive therapy — what ecology says happens when you remove the dominant species, Hypothesis: adaptive scheduling of menin inhibitors will fail, because MEN1 resistance mutations probably cost the cell nothing
257. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28449087
     Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner.

     Zhang P, Rausch C, et al. · Nucleic Acids Res 2017
     used by CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, Is the CpG address a contested resource? On current evidence, no - and the beat that went looking says so, MBD1 - one protein with a methyl-CpG reader and three CXXC fingers, only the third of which binds unmethylated CpG, and whose CXXC fails the MLL-AF9 swap
258. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28355567
     SIRT6 Is Essential for Adipocyte Differentiation by Regulating Mitotic Clonal Expansion.

     Chen Q, Hao W, Xiao C, Wang R, Xu X, Lu H, Chen W, Deng CX · Cell Rep 2017
     used by CSNK2A2 - CK2's other catalytic subunit, expressed in every KMT2A-rearranged line and, if anything, slightly favourable to lose
259. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28319062
     CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic.

     Marshall AD, Bailey CG, Champ K, Vellozzi M, O'Young P, Metierre C, Feng Y, Thoeng A, Richards AM, Schmitz U, Biro M, Jayasinghe R, Ding L, Anderson L, Mardis ER, Rasko JEJ · Oncogene 2017
     used by CTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients
260. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29033304
     Epigenetic Activation of Pro-angiogenic Signaling Pathways in Human Endothelial Progenitors Increases Vasculogenesis

     · Stem Cell Reports 2017
     used by CXCR4 - named in eighteen entries of this graph with no entry of its own, and the one niche molecule with a drug, a paediatric trial and a direct KMT2A-r experiment
261. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28416650
     Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs.

     Ma S, Wan X, et al. · J Exp Med 2017
     used by CXXC5 (RINF) - the one CXXC reader measurably down-regulated in KMT2A-rearranged AML, which is the only direction-of-change any family member has in this disease, TET2 is NOT a CXXC protein - its CXXC domain is a separate gene, and it is DEPLETED in KMT2A-rearranged AML rather than enriched
262. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 28341773
     PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX

     Delbarre E, ..., Collas P · Genome Research 2017
     used by DAXX - the strongest of five selective dependencies among 254 unwritten interactors but it FAILS Bonferroni correction (p=0.0128, rank 4 of 254), and not one paper connects it to this disease
263. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28875424
     Structural basis for DAXX interaction with ATRX.

     Wang X, Zhao Y, Zhang J, et al. · Protein & Cell 2017
     used by DAXX and ATRX as drug targets: six ChEMBL rows and zero of them an affinity, against menin's 1,776 - but three crystal structures of the interface that would have to be blocked
264. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29083303
     Deep transcriptome annotation enables the discovery and functional characterization of cryptic small proteins.

     Samandi S, Roy AV, Delcourt V, et al. · eLife 2017
     used by DDIT3 / CHOP (P35638) - the cascade's middle node, and the symbol whose two reviewed human records and 16,893-record alias are the worst identifier trap in this beat
265. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28216671
     Dual mechanisms regulate the nucleocytoplasmic localization of human DDX6.

     Huang JH, Ku WC, Chen YC, Chang YL, Chu CY · Sci Rep 2017
     used by DDX6 - the only protein ever proposed to do for a cell what Tat does for the virus, on the strength of one 2016 paper
266. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28202522
     Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis

     Valerio DG, Xu H, Chen CW, Hoshii T, Eisold ME, Delaney C, Cusan M, Deshpande AJ, Huang CH, Lujambio A, Zheng YG, Zuber J, Pandita TK, Lowe SW, Armstrong SA · Cancer Research 77(7):1753-1762 2017
     used by Does the fusion 'lose restraint'? The pattern of KMT2A-side loss, and why the tidy reading does not survive contact with the ledger, H4K16ac - the one mark rule 80 actually rescued in this beat: elevated at MLL-AF9 targets in a supplementary figure, and the reason MLL1's own enzyme turns out to be dispensable, Ledger: every module the KMT2A half loses, with coordinates, how each was confirmed, and whether its loss has been shown to matter, Lost from the KMT2A half: the MOF/KAT8 contact - required in the cell, but not shown to matter to the fusion, MOF/KAT8 is required by both KMT2A::MLLT3 and NUP98::HOXA9 — which is why it is the wrong kind of convergence, MSL1 - the MSL scaffold that carries MOF and MSL2 to HOXA9 and MEIS1, with zero records against KMT2A and a mapped, drawable domain architecture, NSL complex - the MOF assembly that five NUP98 fusions bind alongside MLL1, and that competes with MLL/COMPASS for WDR5
267. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28241139
     Transcription control by the ENL YEATS domain in acute leukaemia.

     Erb MA, Scott TG, Li BE, Xie H, et al. · Nature 2017
     used by Does the fusion's programme fall apart in the same order in KMT2A::AFF1 as in MLL::AF9? The chain's only ordering measurement, repeated on the index fusion, KMT2A::MLLT1 (MLL-ENL), t(11;19)(q23;p13.3), KMT2A::MLLT1 engages P-TEFb through one 66-residue surface: the ENL AHD, residues 494-559, and L550E breaks it, MLLT1 / ENL — the reader that beat its own paralogue, with a degrader already in hand, Reversibility and kinetics — does the program collapse when the fusion is removed, and how fast?
268. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28241141
     ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia.

     Wan L, Wen H, Li Y, et al. · Nature 2017
     used by DOT1L and H3K79 in KMT2A::MLLT3: recruitment is a graded dial that sets methylation and transformation - and the fusion it was discovered in produced no remission in the DOT1L trial, How a spliced fusion works: the break lands in front of MLLT1, the gene is never cut, and there is nothing left to make a reciprocal product from, Hypothesis: YEATS-pocket occupancy disables the reader module of all three SEC-family complexes in proportion to how much of the reader pool each holds — so the drug's footprint is set by an unmeasured partition, not by the fusion, KMT2A::MLLT1 (MLL-ENL), t(11;19)(q23;p13.3), KMT2A::MLLT1 versus KMT2A::MLLT3: paralogous partners whose chromosomes break on opposite sides of the same domain, MLLT1 (ENL) refutes the YEATS parallel: the reader is retained in 84% of patients and is required for leukemogenesis, MLLT1 / ENL — the reader that beat its own paralogue, with a degrader already in hand, MLLT3 (AF9): the YEATS acetyl-lysine reader is discarded in ~92% of MLL-AF9 patients — same shape as PZP, but the causal test has never been run, MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is, Scored against the literature: the composition half of the YEATS-selectivity objection holds and the selectivity half is refuted — a scaffold-blind probe already has an in vivo window in the index fusion with no HSPC toxicity, The 2x2 paralogue swap: separate 'is the reader there' from 'which backbone is it on', in one background with matched expression, The ENL YEATS acetyl-reader inside KMT2A::MLLT1: what it reads, what it does, and why both control arms carry it, The partner-matched control arm is not 241 versus 219 - it is 153 versus 101, and in that subset the two groups make an identical fusion protein, Two surfaces, two jobs: the AHD picks the scaffold and the YEATS pocket reads the histone — so a YEATS ligand cannot ask which of the three SEC-family complexes it is disabling, Where t(9;11) actually breaks inside MLLT3: 98.4% downstream of exon 4, and the two patients in 442 who kept the reader
269. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28135235
     An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED.

     Qi W, Zhao K, Gu J, Huang Y, Wang Y, Zhang H, et al. · Nat Chem Biol 2017
     used by EED - the PRC2 subunit this disease actually needs, with drugs in the clinic and zero leukaemia studies, Point the EED inhibitor at the index fusion - a clinical-stage drug, a subunit with no paralogue, and zero leukaemia experiments, SUZ12 - the scaffold that holds PRC2 together and decides which PRC2 it is, required in this disease and studied in it exactly once
270. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28858629
     Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival.

     Alexander LMM, Watters J, Reusch JA, Maurin M, Nepon-Sixt BS, Vrzalikova K, Alexandrow MG, Murray PG, Wright KL · Mol Immunol 2017
     used by ELL2 — a SEC subunit that almost no cell needs, next to a paralogue almost every cell needs, Plasma cell - the end of the B lineage, and the only cell type in which ELL2 has a documented job
271. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28134250
     Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription

     Qi S, Li Z, Schulze-Gahmen U, Stjepanovic G, Zhou Q, Hurley JH · Nat Commun 8:14076 2017
     used by ELL2 — domain architecture and residue coordinates, The ELLbow: AFF4 301-351 wrapped over the ELL2 occludin domain at 2.0 A, Kd 86 nM - and no structure of ELL itself, the partner in t(11;19)
272. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28588020
     Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.

     Stein EM, DiNardo CD, Pollyea DA, et al. · Blood 2017
     used by Enasidenib - an approved mutant-IDH2 inhibitor sitting next to the one methylome co-mutation that IS enriched in KMT2A-rearranged AML, and never tested there
273. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27856324
     MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation

     Godfrey L, Kerry J, Thorne R, et al. (Milne TA, senior author) · Experimental Hematology 47:64-75 2017
     used by Enhancer usage in KMT2A-rearranged leukemia — occupancy and amplification, not hijacking, and not super-enhancers, H3K27ac - named in 40 entries with no entry of its own, and the strongest KMT2A::AFF1 measurement of it is invisible to every abstract search, Polycomb in KMT2A-r leukemia — core PRC2 required, EZH2 and BMI1 dispensable, and CBX8 acting outside its repressive role, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133, Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question
274. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27813122
     Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements.

     Biechonski S, Gourevich D, Rall M, Aqaqe N, Yassin M, Zipin-Roitman A, et al. · Int J Cancer 2017
     used by Etoposide (VP-16) - the drug that makes this disease and cures several others, and the only entry in this graph whose main finding is that you must not stop using it, Hypothesis: what breaks KMT2A in a fetus is TOP2B doing its normal transcription-coupled job in a non-cycling progenitor, with no poison involved and repair capacity as the rate-limiting variable
275. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 28299660
     ETV6-RUNX1 Acute Lymphoblastic Leukaemia in Identical Twins

     Ford AM, Greaves M · Adv Exp Med Biol 2017
     used by ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
276. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28741798
     Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

     Honma D, Kanno O, Watanabe J, Kinoshita J, Hirasawa M, Nosaka E, et al. · Cancer Sci 2017
     used by EZH1 - the paralogue that makes the approved EZH2 drug the wrong drug for this disease, EZH2 - the Polycomb enzyme that collaborates with the fusion instead of opposing it, and that no single-agent inhibitor can switch off, Valemetostat - an approved dual EZH1/EZH2 inhibitor that has already worked in an MLL-AF4 xenograft, in a disease nobody has enrolled it in
277. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28453857
     Fbxl19 recruitment to CpG islands is required for Rnf20-mediated H2B mono-ubiquitination.

     Lee BK, Lee J, et al. · Nucleic Acids Res 2017
     used by FBXL19 - a CpG-island reader that delivers CDK-Mediator and RNF20 to developmental promoters, and whose experimental localisation is mostly cytoplasm
278. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29290585
     A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1.

     Böiers C, Richardson SE, Laycock E, Zriwil A, Turati VA, Brown J, Wray JP, Wang D, James C, Herrero J, Sitnicka E, Karlsson S, Smith AJH, Jacobsen SEW, Enver T · Dev Cell 2017
     used by Fetal-restricted permissive factors across fusion families - the class has exactly ONE fully worked member, and for ETV6::RUNX1 the fetal advantage is real but no factor is named
279. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27870947
     Subcellular localization of the FLT3-ITD oncogene plays a significant role in the production of NOX- and p22phox-derived reactive oxygen species in acute myeloid leukemia.

     Moloney JN, Stanicka J, Cotter TG · Leuk Res 2017
     used by FLT3-ITD signals from inside the cell, not from the surface - and whether it is the ER or the Golgi decides which pathway fires
280. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28017614
     FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N(6)-Methyladenosine RNA Demethylase

     Li Z, et al. · Cancer Cell 2017
     used by FTO — highly expressed in MLL-rearranged AML, and the single flattest dependency row in this beat: 0.2% of 1,208 lines
281. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28211977
     1q21.3 deletion involving GATAD2B: An emerging recurrent microdeletion syndrome.

     Tim-Aroon T, Jinawath N, Thammachote W, Sinpitak P, Limrungsikul A, Khongkhatithum C, Wattanasirichaigoon D · American Journal of Medical Genetics Part A 2017
     used by GATAD2B / p66-beta (Q8WXI9) - the NuRD scaffold with the broadest presence in the pan-MLL-fusion interactome, five of seven baits and still not the index fusion, and a haploinsufficiency syndrome that caps any therapeutic idea
282. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29147018
     Enforced GFI1 expression impedes human and murine leukemic cell growth

     Hones JM, Thivakaran A, Botezatu L, Patnana P, Castro SVDC, Al-Matary YS, Schutte J, Fischer KBI, Vassen L, Gorgens A, Duhrsen U, Giebel B, Khandanpour C · Scientific Reports 7:15720 2017
     used by GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way
283. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28698370
     G9a coordinates with the RPA complex to promote DNA damage repair and cell survival.

     Yang Q, Zhu Q, Lu X, Du Y, Cao L, et al. · Proceedings of the National Academy of Sciences 2017
     used by Giving a G9a/GLP inhibitor alongside etoposide or doxorubicin removes a DNA-repair licence at the moment TOP2 breaks are being made - and the sibling compound UNC-0638 is measured to block BRCA1/BARD1 arrival at a break, in children on curative therapy, The CTCF licensing cascade: CTCF recruits HP1-gamma, KAP1, SUV39H1, SETDB1 and KDM5A to a break, that repressive chromatin licenses EARLY BRCA1/BARD1, and early BRCA1/BARD1 licenses EXO1/DNA2 long-range resection - measured entirely in U2OS and HEK-293T, with engineered breaks and one etoposide arm
284. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27150106
     Loss of Drosophila nucleostemin 2 (NS2) blocks nucleolar release of the 60S subunit leading to ribosome stress.

     Wang Y, DiMario P · Chromosoma 2017
     used by GNL2 / Ngp-1 (Q13823) - a nucleostemin-family nucleolar GTPase in the MLL-fusion nucleolar block, in the index fusion's column at p = 0.0492, and the one member with a published granular-component assignment
285. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28612833
     Variant in the X-chromosome spliceosomal gene GPKOW causes male-lethal microcephaly with intrauterine growth restriction.

     Carroll R, et al. · Eur J Hum Genet 2017
     used by GPKOW - a G-patch spliceosomal protein whose BioID neighbourhood contains AFF4, ELL, ENL, CDK9, KMT2A and DOT1L
286. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27777140
     Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis.

     Ruggeri A, Volt F, Locatelli F, Michel G, Diaz de Heredia C, Abecasis M, Zecca M, Vora A, et al. · Biology of Blood and Marrow Transplantation 2017
     used by Graft-versus-host disease in a transplanted infant - the only antileukaemic benefit and the main cause of death are the same process at different grades, Graft-versus-leukaemia in KMT2A-rearranged infant leukaemia - the mechanism the whole transplant rests on, demonstrated in ALL generally, assumed in this disease, and with a published mechanistic reason to doubt it
287. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28114278
     MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia.

     Prange KHM; Mandoli A; Kuznetsova T; Wang SY; Sotoca AM; Marneth AE; et al. · Oncogene 2017
     used by H3K27ac - named in 40 entries with no entry of its own, and the strongest KMT2A::AFF1 measurement of it is invisible to every abstract search, RUNX1 — activated by KMT2A::AFF1 and then bound by the reciprocal fusion, in the one published two-oncoprotein circuit in t(4;11)
288. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28867287
     Dynamic Control of X Chromosome Conformation and Repression by a Histone H4K20 Demethylase.

     Brejc K, et al. · Cell 2017
     used by H4K20me2 - the abundant repair-linked H4 mark, the 53BP1 docking site, and the first H4K20 state in this graph; never once measured in a KMT2A-rearranged cell, RSBN1 / KDM9 (Q5VWQ0) - an H4K20me2/me3 demethylase in the AFF4 proximity record, and the only read-queue partner that is a chromatin enzyme at all
289. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28712728
     HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response.

     Morchikh M, et al. · Mol Cell 2017;67:387-399.e5 2017
     used by HEXIM1 - the brake pad, the only part of the reservoir anyone has deliberately raised in a KMT2A-rearranged cell, and the result was that the leukaemia grew less, SFPQ / PSF (P23246) - the last of 21 fusion-construct partners without an entry, and it is itself the 5' half of an ALL fusion that puts ABL1 in the nucleus
290. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28180285
     Reciprocal regulation of chromatin state and architecture by HOTAIRM1 contributes to temporal collinear HOXA gene activation

     Wang XQD, Dostie J · Nucleic Acids Research 45(3):1091-1104 2017
     used by HOTAIRM1 lncRNA — the myeloid-differentiation transcript at the 3' end of HOXA, with a KMT2A-r evidence gap
291. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28920958
     The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells

     Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, Schulman J, Famulare C, Patel M, Klimek VM, Garrett-Bakelman FE, Melnick A, Carroll M, Mason CE, Jaffrey SR, Kharas MG · Nature Medicine 2017
     used by Hypothesis: transfer-RNA and ribosome biology is a genuinely empty cell in KMT2A-rearranged leukemia, and translational capacity may be the unmeasured dependency, METTL3 — the m6A writer with a clinical-grade inhibitor, an MLL-rearranged AML mechanism, and a B-lymphoid signal that goes the wrong way, RNA m6A (METTL3/YTHDF/YTHDC1) in KMT2A-rearranged leukemia — the empty cell that turned out not to be empty, The RNA layer scored for KMT2A-selectivity across 79 genes, lineage-split — PTBP1 is the only menin-shaped hit, and the IGF2BP family shows no co-dependency
292. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28254838
     The 7SK snRNP associates with the little elongation complex to promote snRNA gene expression

     Egloff S, Vitali P, Tellier M, Raffel R, Murphy S, Kiss T · EMBO Journal 36(7):934-948 2017
     used by ICE1 — the 2,266-residue scaffold of the little elongation complex, the subunit that acts at initiation, and zero papers connecting it to leukaemia of any kind, ICE2 — the fourth LEC subunit, the one with no assigned step, no structure, and no leukaemia literature, The little elongation complex (ELL + ICE1 + ICE2 + ZC3H8) — the other place ELL works, and why ELL's pan-essentiality is probably not about the fusion, ZC3H8 / Fliz1 - the last little-elongation-complex subunit without an entry, discovered in fetal liver haematopoietic progenitors, and a selective BioID2 bait that reaches KMT2A in K562
293. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27992417
     Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

     Meyer E, Carss KJ, Rankin J, et al. · Nat Genet 2017
     used by In a cell with no fusion, a menin inhibitor is substantially a KMT2B drug, KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote, Menin holds KMT2A and KMT2B, and the graph has been written as if it held one
294. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28106886
     Loss of menin in osteoblast lineage affects osteocyte-osteoclast crosstalk causing osteoporosis.

     Liu P, Lee S, Knoll J, Rauch A, Ostermay S, Luther J, et al. · Cell Death and Differentiation 2017
     used by In a live mouse, losing menin in bone cells means less bone - and menin overexpression means more
295. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28031410
     Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma.

     Zhu F, Hwang B, Miyamoto S, Rui L · Mol Cancer Res 2017
     used by JAK1 - recruited and stabilised by AF10 fusions, and the kinase whose downstream STAT1 the class I effect of menin inhibition explicitly does not need
296. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29211711
     KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.

     Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, Tan L, Yang P, Lee JH, Li XJ, Hawke D, Zheng Y, Qian X, Lyu J, He J, Xing D, Tao YJ, Lu Z · Nature 2017
     used by KAT2A / GCN5 - the SAGA catalytic subunit that reaches this disease through its complex rather than through its own symbol, and whose only chemical tool degrades its paralogue too
297. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28334966
     Structural and mechanistic insights into regulation of HBO1 histone acetyltransferase activity by BRPF2

     Tao Y, Zhong C, Zhu J, et al. · Nucleic Acids Research 2017
     used by KAT7 / HBO1 — an enzyme, a leukaemia-stem-cell dependency, and an inhibitor already in a crystal
298. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27827827
     Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice.

     Valerio DG, Xu H, et al. · Blood 2017
     used by KAT8/MOF sets the quiescence set-point of the blood stem cell - and its catalytic activity is separately required for MLL-AF9 leukaemia, which DepMap also cannot see
299. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27588400
     MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations

     Kerstjens M, Driessen EMC, Willekes M, Pinhanços SS, Schneider P, Pieters R, Stam RW · Oncotarget 8(9):14835-14846 2017
     used by Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal, KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells, NF1 in KMT2A-r leukemia — one homozygous deletion, one missense, and the only loss-of-function co-lesion in the disease, NRAS as a co-mutation in KMT2A-r leukemia — the one co-lesion that is specifically enriched in t(4;11), Treating a subclonal lesion is selection pressure applied to the clone you did not aim at
300. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28394257
     Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia.

     Okuda H, Stanojevic B, Kanai A, Kawamura T, Takahashi S, Matsui H, Takaori-Kondo A, Yokoyama A · J Clin Invest 2017
     used by KMT2A::AFF1 has no mapped interface to DOT1L: it lacks both structurally defined recruitment modules, and the one complex-level route claimed for it is contested by reconstitution
301. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28637661
     The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment.

     Lin S, Luo RT, et al. · Blood 2017
     used by KMT2A::AFF1 needs a developmental window and a lymphoid-committed cell — the cell type is a condition of transformation, not a consequence of it
302. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28535805
     First case of B ALL with KMT2A-MAML2 rearrangement: a case report.

     Menu E, Beaufils N, Usseglio F, Balducci E, Lafage Pochitaloff M, Costello R, Gabert J · BMC Cancer 2017
     used by KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour, MAML2 exon 2: the strongly preferred 3' acceptor, the same in leukaemia, thymoma and salivary-gland tumours
303. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28609655
     MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia.

     Chen Y, Anastassiadis K, Kranz A, et al. · Cancer Cell 2017
     used by KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote, MLL2 and MLL4 each name two different genes, and the ambiguity is in the papers, not in the databases, The lost SET domain, and the verdict: the fusion is a gain-of-function neomorph, not a KMT2A loss-of-function, The third category: modules lost from the fusion protein but supplied in trans by the wild-type KMT2A allele, When a family shares a complex, the result is family-selective, not member-selective - the protein version of this graph's inhibitor-class rule
304. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28069604
     KMT2E-ASNS: a novel relapse-specific fusion gene in early T-cell precursor acute lymphoblastic leukemia.

     Khater F, Lajoie M, Langlois S, et al. · Blood 2017
     used by KMT2E (MLL5) - the family member with a dead SET domain, and the exclusion from COMPASS is justified
305. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 28188343
     MLL5 (KMT2E): structure, function, and clinical relevance.

     Zhang X, Novera W, Zhang Y, Deng LW · Cell Mol Life Sci 2017
     used by KMT2E (MLL5) - the family member with a dead SET domain, and the exclusion from COMPASS is justified
306. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28428443
     Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia.

     Campbell CT, Haladyna JN, Drubin DA, Thomson TM, et al. · Mol Cancer Ther 2017
     used by KOPN-8 (CVCL_1866): the field's default KMT2A::MLLT1 line, and its fusion protein has no YEATS domain, Step 4 — The histone mark: DOT1L and H3K79me2/3 at fusion target genes (and why global expression barely moves), Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
307. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28619714
     The G protein-coupled receptor GPR31 promotes membrane association of KRAS.

     Fehrenbacher N, Tojal da Silva I, Ramirez C, Zhou Y, Cho KJ, Kuchay S, Shi J, Thomas S, Pagano M, Hancock JF, Bar-Sagi D, Philips MR · J Cell Biol 2017
     used by KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells
308. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29239724
     SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a.

     Jing H, Zhang X, Wisner SA, Chen X, Spiegelman NA, Linder ME, Lin H · Elife 2017
     used by KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells
309. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28693523
     Inhibition of LIN28B impairs leukemia cell growth and metabolism in acute myeloid leukemia.

     Zhou J, Bi C, Ching YQ, Chooi JY, Lu X, Quah JY, Toh SH, Chan ZL, Tan TZ, Chong PS, Chng WJ · J Hematol Oncol 2017
     used by LIN28B and IGF2BP3 are co-regulated members of ONE onco-fetal module in infant leukaemia - which strengthens the graph's existing scepticism about IGF2BP3 rather than weakening it, LIN28B has THREE published signs in myeloid leukaemia - oncogene, tumour suppressor, and differentiation agent - and the design quality runs opposite to the direction the index-fusion story needs, LIN28B has two routes - blocking let-7, and binding mRNAs directly - and in KMT2A::AFF1 every published mechanism is the direct-mRNA one (let-7 IS measured in mouse MLL-fusion AML: in-session correction)
310. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28329763
     The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.

     Wylie AA, Schoepfer J, Jahnke W, et al. · Nature 2017
     used by Mechanism class 3 — constitutive kinase activation (BCR::ABL1, NPM1::ALK, ETV6::NTRK3), Why BCR::ABL1 became treatable — and what KMT2A::AFF1 does not share with it
311. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28446439
     PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability

     Gryder BE, Yohe ME, Chou HC, et al. · Cancer Discovery 2017
     used by Mechanism class 4 — condensate-driven transcriptional rewiring (NUP98-r, EWSR1::FLI1)
312. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28765911
     LCMR1 interacts with DEK to suppress apoptosis in lung cancer cells.

     Xu Y, Liang Z, Li C, et al. (5 authors; senior author Chen L) · Mol Med Rep 2017
     used by MED19 - the Mediator subunit curated against an engineered MLL-AFF4 fusion protein, and the one REST uses to deliver G9a
313. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28112737
     Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

     de Rooij JD, Branstetter C, Ma J, Li Y, Walsh MP, Cheng J, et al., Gruber TA · Nature Genetics 2017
     used by Megakaryocyte-erythroid progenitor (MEP) — the branch KMT2A fusions almost never take, which is why it was a usable control
314. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28473536
     Impact of cytosine methylation on DNA binding specificities of human transcription factors.

     Yin Y, Morgunova E, Jolma A, et al. · Science 2017
     used by MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed
315. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28007956
     Upregulation of RPA2 promotes NF-kappaB activation in breast cancer by relieving the antagonistic function of menin on NF-kappaB-regulated transcription.

     Chen CC, Juan CW, Chen KY, Chang YC, Lee JC, Chang MC · Carcinogenesis 38(2):196-206 2017
     used by Menin binds RPA2 directly, the contact maps to RPA2 aa 43-171 across its low-affinity ssDNA site, and three MEN1 patient missense mutations abolish it - a 2003 finding that this graph had never cited despite menin being its central node, Menin represses NF-kB transactivation — through a mapped central region, a SIRT1 cofactor, and an RPA2 off-switch, in every tissue except the one this project cares about, RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin, RPA2 (RPA32) - the middle subunit of replication protein A, whose disordered N-terminus is the phospho-switch of the replication-stress response and whose 43-171 region binds menin
316. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28270438
     Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB.

     Muhammad AB, Xing B, Liu C, Naji A, et al. · American Journal of Physiology - Endocrinology and Metabolism 2017
     used by Menin represses GLP1R - the receptor a whole class of diabetes drugs exists to switch on, The same drug target, pursued for benefit: menin inhibition is a diabetes strategy in the literature
317. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28331056
     Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology.

     Hovorkova L, Zaliova M, Venn NC, et al. · Blood 2017
     used by MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction
318. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28436985
     Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells

     Vu LP, et al. · Nat Genet 2017
     used by MSI2 (Musashi-2) — sustains the MLL stem-cell programme in mouse, and the myeloid DepMap arm disagrees in sign, SYNCRIP (hnRNP Q) — required for MLL leukaemia stem cells in one paper and a tumour suppressor deleted in T-ALL in another, The decisive experiment: acute degron removal of IGF2BP3, IGF2BP2 and both, read on self-renewal and xenograft initiation rather than bulk dropout
319. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29094699
     Two independent modes of chromatin organization revealed by cohesin removal.

     Schwarzer W, Abdennur N, Goloborodko A, Pekowska A, Fudenberg G, Loe-Mie Y, et al. · Nature 2017
     used by NIPBL - the cohesin loader, the cleanest degron result in the whole architecture literature, and a second bounded absence in this disease
320. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28787259
     Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children's Oncology Group Study

     Mossé YP, Voss SD, Lim MS, et al. · Journal of Clinical Oncology 2017
     used by NPM1::ALK (NPM-ALK), t(2;5)(p23;q35)
321. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 29269482
     Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells

     Franks TM, McCloskey A, Shokirev MN, Benner C, Rathore A, Hetzer MW · Genes Dev 2017
     used by NUP98 - the mobile nucleoporin that leaves the pore to put H3K4me3 on haematopoietic promoters, and the shared 5' donor of seven fusions in this graph
322. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28221134
     Human Nup98 regulates the localization and activity of DExH/D-box helicase DHX9

     Capitanio JS, Montpetit B, Wozniak RW · eLife 2017
     used by NUP98 - the mobile nucleoporin that leaves the pore to put H3K4me3 on haematopoietic promoters, and the shared 5' donor of seven fusions in this graph
323. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27694926
     NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis

     Struski S, et al. · Leukemia 31(3):565-572 2017
     used by NUP98 rearrangements are 7.2% of paediatric AML and 1.6% of adult, with 35% five-year overall survival — and the partner changes everything
324. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28484033
     Ectopic protein interactions within BRD4-chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

     Alekseyenko AA, Walsh EM, Zee BM, et al. · Proceedings of the National Academy of Sciences 2017
     used by NUTM1 (NUT) - a testis-restricted, fully disordered protein that writes no mark and instead switches ON a writer, and the 3' partner of the KMT2A-wild-type infant B-ALL with the opposite prognosis
325. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28340332
     Super elongation complex promotes early HIV transcription and its function is modulated by P-TEFb.

     Kuzmina A, et al. · Transcription 2017
     used by P-TEFb phosphorylates AFF4 and rearranges the complex the fusion hijacks
326. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29296788
     MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs.

     Maifrede S, Martinez E, Nieborowska-Skorska M, Di Marcantonio D, Hulse M, Le BV, et al. · Blood Adv 2017
     used by PARP1 - the target whose inhibitors this disease was specifically shown to resist, and which three later papers combine anyway
327. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28886273
     PARPi potentiates with current conventional therapy in MLL leukemia.

     Zhao L, So CWE · Cell Cycle 2017
     used by PARP1 - the target whose inhibitors this disease was specifically shown to resist, and which three later papers combine anyway
328. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28411381
     PBX3 is essential for leukemia stem cell maintenance in MLL-rearranged leukemia

     Guo H, Chu Y, Wang L, Chen X, Chen Y, Cheng H, Zhang L, Zhou Y, Yang FC, Cheng T, Xu M, Zhang X, Zhou J, Yuan W · International Journal of Cancer 141:324-335 2017
     used by PBX3 - the TALE cofactor the field says is non-redundant, and the experiment that says HOXA9 is the redundant one
329. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28428369
     Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

     Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, et al., Hacohen N · Science 2017
     used by Plasmacytoid dendritic cell — the interferon cell that KMT2A-rearranged leukaemia occasionally becomes, and is more often mistaken for
330. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28851805
     C-terminal motifs in promyelocytic leukemia protein isoforms critically regulate PML nuclear body formation.

     Li C, Peng Q, Wan X, Sun H, Tang J · J Cell Sci 2017
     used by PML / TRIM19 (P29590) - the scaffold of PML nuclear bodies, co-purified with all seven MLL fusions, and never once studied as a KMT2A-fusion partner
331. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28409853
     A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03)

     Cooper TM, Sison EAR, Baker SD, Li L, Ahmed A, Trippett T, Gore L, Macy ME, et al. · Pediatric Blood and Cancer 2017
     used by POE 10-03 / NCT01319864 — the only completed paediatric trial of niche disruption, which mobilised blasts 3.4-fold and produced three responses in nineteen children, none of them in ALL
332. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28077417
     Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

     Kunimoto H, McKenney AS, Meydan C, et al. · Blood 2017
     used by Programmed DNA breaks - V(D)J and class switching - and the verdict on whether either one breaks KMT2A
333. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 34541330
     H3K36me3 and PSIP1/LEDGF associate with several DNA repair proteins, suggesting their role in efficient DNA repair at actively transcribing loci.

     Sundarraj J, Taylor GCA, et al. · Wellcome Open Res 2017
     used by PSIP1 keeps R-loops off the genes it sits on, and removing it causes transcription-replication conflict, DNA damage and PARP-inhibitor sensitivity, The bite-back surface: LEDGF tethers CtIP to active chromatin and is required for DNA-end resection and homologous recombination
334. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28834754
     SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination.

     Daddacha W, Koyen AE, Bastien AJ, Head PE, Dhere VR, Nabeta GN, et al. · Cell Rep 2017
     used by SAMHD1 - the dNTP hydrolase that is the real biomarker behind the IMPDH story, and the reason the KMT2A framing of that story does not hold
335. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28180295
     A permissive chromatin state regulated by ZFP281-AFF3 in controlling the imprinted Meg3 polycistron.

     Wang Y, Shen Y, Dai Q, Yang Q, Zhang Y, Wang X, Xie W, Luo Z, Lin C · Nucleic Acids Research 2017
     used by SEC-L3 — the AFF3-scaffolded complex, and the only SEC-family member with a known physiological job: genomic imprinting and X inactivation
336. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28369034
     SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPɛ dependent mechanism.

     Priam P, Krasteva V, Rousseau P, D'Angelo G, Gaboury L, Sauvageau G, Lessard JA · Nat Genet 2017
     used by SMARCD2 (BAF60B) - named in one KMT2A paper in the whole of PubMed, and the dependency it carries is myeloid identity, not the rearrangement
337. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 28369036
     Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes.

     Witzel M, Petersheim D, Fan Y, Bahrami E, Racek T, Rohlfs M, Puchałka J, Mertes C, Gagneur J, Ziegenhain C, Enard W, Stray-Pedersen A, Arkwright PD, Abboud MR, Pazhakh V, Lieschke GJ, Krawitz PM, Dahlhoff M, Schneider MR, Wolf E, Horny HP, Schmidt H, Schäffer AA, Klein C · Nat Genet 2017
     used by SMARCD2 (BAF60B) - named in one KMT2A paper in the whole of PubMed, and the dependency it carries is myeloid identity, not the rearrangement
338. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28436581
     Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan

     Yen HJ, Chen SH, Chang TY, Yang CP, Lin DT, Hung IJ, Lin KH, Chen JS, Hsiao CC, Chang TT, Chang TK, Peng CT, Lin MT, Jaing TH, Liu HC, Jou ST, Lu MY, Cheng CN, Sheen JM, Chiou SS, Hung GY, Wu KH, Yeh TC, Wang SC, Chen RL, Chang HH, Yang YL, Chen SH, Cheng SN, Chang YH, Chen BW, Hsieh YL, Huang FL, Ho WL, Wang JL, Chang CY, Chao YH, Lin PC, Chen YC, Liao YM, Lin TH, Shih LY, Liang DC · Pediatr Blood Cancer 2017
     used by TCF3::PBX1 (E2A-PBX1), t(1;19)(q23;p13.3)
339. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28531272
     A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer.

     Good CR, Madzo J, et al. · Nucleic Acids Res 2017
     used by TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
340. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 28798069
     MLL-TET1 fusion protein promotes immortalization of myeloid progenitor cells and leukemia development.

     Kim HS, Oh SH, et al. · Haematologica 2017
     used by TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
341. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28471724
     Economic Burden of Chronic Conditions Among Survivors of Cancer in the United States

     Guy GP Jr, Yabroff KR, Ekwueme DU, Rim SH, Li R, Richardson LC · Journal of Clinical Oncology 2017
     used by The cost of surviving: late effects carry a lifetime bill nobody has costed for infants
342. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 28677575
     From class waivers to precision medicine in paediatric oncology

     Pearson ADJ, Pfister SM, Baruchel A, Bourquin JP, Casanova M, Chesler L, Doz F, Eggert A, Geoerger B, Jones DTW, Kearns PR, Molenaar JJ, Morland B, Schleiermacher G, Schulte JH, Vormoor J, Marshall LV, Zwaan CM, Vassal G · The Lancet Oncology 18(7):e394-e404 2017
     used by The EU paediatric investigation plan: an obligation, not an incentive - and the deferral is the loophole
343. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 29796335
     TALEN-Mediated FLAG-Tagging of Endogenous Histone Methyltransferase DOT1L.

     An C, Zhu G, Martos SN, et al. · Advances in bioscience and biotechnology (Print) 2017
     used by The five verdicts in one place, plus what this beat read and did not use
344. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.datasetPMID 28301528
     GSE71809 RSEG ENRICHED-domain BED files for 31 samples, parsed over hg19 intervals with per-sample chromosome-wide domain-coverage nulls, a same-width window null and a chr11 gap-length ranking, 2026-09-22; code and full per-sample output at analyses/q111-cd34-h3k9me2-over-the-kmt2a-bcr/run.py, nulls.py, results.json and results_nulls.json

     Salzberg AC, Harris-Becker A, Popova EY, Keasey N, Loughran TP, Claxton DF, Grigoryev SA · NCBI GEO (data accompanying PLoS One 12:e0173723) 2017
     used by The KMT2A locus sits inside a 179-318 kb H3K9me2-domain-free block in human CD34+ bone-marrow progenitors - the 7th, 11th and 37th longest such block on chr11 in three ChIPs - and the same block is present in granulocytes, K562 and most primary AML, The off-target surface, measured rather than feared: KDM3B depletion moves CTCF occupancy at 84.6% of 12,443 RPE anchors and halves it at 1,436 - so an H3K9-axis drug given to prevent one rearrangement is remodelling loop architecture genome-wide, and preferentially at the strongest anchors, The resting-state H3K9me2 depletion over KMT2A DOES replicate in a human CD34+ haematopoietic progenitor - measured in 3 of 3 progenitor ChIPs, where the locus sits in the 7th, 11th and 37th longest H3K9me2-free gap on chr11 - but it is not a progenitor property: granulocytes, K562 and 6 of 10 primary AML samples show the same gap, The third resolution trap in three cycles: an ENRICHED-domain BED has a median domain of 13-17 kb and a per-SAMPLE bin size, so 'the GAPDH promoter is inside an H3K9me3 domain' is true in the file and means nothing about the promoter
345. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     IGVTools 2.3.98 (igvtools.jar), org.broad.igv.tdf.TDFReader / TDFDataset / TDFTile

     · Broad Institute 2017
     used by The premise that GSE260742 'carries a ChIP-Rx spike-in' does not survive reading the deposit: zero of 158 sample records mention a spike-in, the only ChIP-Rx experiment in the paper is an H2AK119ub panel that is not identifiable among the deposited samples, and 152 of 158 samples ship only an unnormalised igvtools .tdf
346. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28420716
     A MEN1 pancreatic neuroendocrine tumour mouse model under temporal control

     Lines KE, Vas Nunes RP, Frost M, Yates CJ, Stevenson M, Thakker RV · Endocrine Connections 2017
     used by The reversibility question: months of partial occupancy against a syndrome built from decades of loss
347. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28825729
     A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor

     · Nature Genetics 2017
     used by The same reader domain, mutated instead of fused, causes a childhood kidney tumour
348. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27872097
     Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase.

     Feng Z, Wang L, Sun Y, et al. · Cancer Res 2017
     used by The SvID, menin 360-445: a truncation boundary the field reads as a domain, whose functional residues D418 and W436 are 10-20 A from every menin drug - but whose first ten residues ARE the drug pocket
349. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28710277
     Phosphorylation of the type II transmembrane serine protease, TMPRSS13, in hepatocyte growth factor activator inhibitor-1 and -2-mediated cell-surface localization.

     Murray AS, Varela FA, Hyland TE et al · Journal of Biological Chemistry 2017
     used by TMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall
350. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28646023
     Amlexanox Downregulates S100A6 to Sensitize KMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNFα Treatment.

     Tamai H, Yamaguchi H, ... Inokuchi K · Cancer Research 2017
     used by TNF — the only NF-kB-activating ligand with real KMT2A::AFF1 B-ALL evidence, and the evidence says the blasts are RESISTANT to it
351. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28474697
     Menin enhances c-Myc-mediated transcription to promote cancer progression.

     Wu G, Yuan M, Shen S, Ma X, Fang J, Zhu L, et al. · Nat Commun 2017
     used by When MYC falls after a menin inhibitor, there are three mechanisms it could be, and no published experiment separates them
352. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 28065413
     Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia.

     Liang K, Volk AG, Haug JS, et al. · Cell 2017
     used by WRAD reaches KMT2A fusions only as a passenger on a recruited wild-type complex
353. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 29224777
     YY1 Is a Structural Regulator of Enhancer-Promoter Loops.

     Weintraub AS, Li CH, Zamudio AV, et al. · Cell 2017
     used by YY1 - the enhancer-promoter looping factor that recovers KMT2A in a 109-transcription-factor BioID screen
354. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27756750
     The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia

     Li H, Mar BG, Zhang H, Puram RV, Vazquez F, Weir BA, Hahn WC, Ebert B, Pellman D · Blood 129:497-508 2017
     used by ZEB2 — an EMT transcription factor that turns out to be a leukemia dependency and a guardian of lineage fidelity
355. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia (GSE74651)

     GEO submitters · NCBI Gene Expression Omnibus 2016
     used by "Diverse models of MLL-rearranged leukaemia" is one mouse cell line: the RNF20 H2Bub requirement resolves to murine RN2 (MLL-AF9/NrasG12D), The Mediator/BET deposition is 48 of 48 mouse MLL-AF9/NrasG12D samples: resolving the KMT2A status behind the MED23 verdict
356. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27119507
     Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair.

     Castaño J, Herrero AB, Bursen A, et al. · Oncotarget 2016
     used by A tested negative: neither fusion product alters DNA double-strand break repair, H2AX - filed as a gene and not as a mark, and the reason that decision changes what the graph can say, Pablo Menendez & Clara Bueno (Josep Carreras Leukemia Research Institute, Barcelona) — cellular origin, fetal models and infant-specific drug resistance, PARP1 - the target whose inhibitors this disease was specifically shown to resist, and which three later papers combine anyway, RAD51 - the one repair protein measured AT the KMT2A translocation hotspot, and ATM controls how much of it loads there
357. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26787460
     Proteomic peptide phage display uncovers novel interactions of the PDZ1-2 supramodule of syntenin.

     Garrido-Urbani S, Garg P, Ghossoub R, Arnold R, Lembo F, Sundell GN, Kim PM, Lopez M, Zimmermann P, Sidhu SS, Ivarsson Y · FEBS Lett 2016
     used by AFF4-SDCBP (syntenin): the only prey-only row in this census typed 'direct interaction' - a proteomic phage-display hit on AFF4's C-terminal peptide, in vitro
358. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26907630
     Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.

     Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. · Blood 2016
     used by After lineage switch, KMT2A-rearranged AML does not merely lose CD19 - it acquires a monocytic myeloid-derived suppressor cell phenotype and actively suppresses T cells, Drug exposure and clonal replacement are completely confounded across this pair - the relapse sample is a different clone in a different lineage, and the paper's own reading is that the drug killed the cells the diagnostic sample was made of, Flow-cytometric MRD: the fastest readout, and the one a lineage switch walks straight out of, Lineage switch as antigen escape from CD19-directed therapy in KMT2A-rearranged leukemia, MRD as a trial endpoint in KMT2A-rearranged leukaemia: high negativity rates, and almost none of them say which assay, Which immune-evasion routes are actually documented in KMT2A-rearranged disease, and which are borrowed from AML and assumed - a ranked ledger with the bounded absences that define it
359. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27824034
     AKAP95 regulates splicing through scaffolding RNAs and RNA processing factors.

     Hu J, Khodadadi-Jamayran A, Mao M, Shah K, Yang Z, Nasim MT, Wang Z, Jiang H · Nat Commun 2016
     used by AKAP8 (AKAP95) - the only nuclear A-kinase anchoring protein, and the one that turned out to be required for MLL-rearranged leukaemia, AKAP95 binds the Pol II CTD directly and nascent RNA gates the condensate - a feed-forward loop where transcription recruits the factor that sustains transcription
360. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26683827
     A-kinase anchoring protein AKAP95 is a novel regulator of ribosomal RNA synthesis.

     Marstad A, Landsverk OJ, Stromme O, Otterlei M, Collas P, Kuntziger T, Kuntziger T · FEBS J 2016
     used by AKAP95's subnuclear addresses - nuclear matrix, nucleolus, and dynamic foci - and the finding that the famous one is the one its MLL-linked function does not need
361. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27462455
     MLL1 and MLL1 fusion proteins have distinct functions in regulating leukemic transcription program.

     Xu J, Li L, Xiong J, et al. · Cell Discov 2016
     used by An anti-MLL-C antibody in a t(4;11) cell is looking at two proteins at once, An anti-MLL-N antibody sees the wild-type allele and the direct fusion, and nothing else - and cannot rank them, Tag endogenous KMT2B in an index-fusion line and measure what revumenib does to it - the experiment the reagents have blocked, WDR5: an established wild-type KMT2A contact, and no fusion contact ever measured
362. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27175594
     The IRX1/HOXA connection: insights into a novel t(4;11)-specific cancer mechanism

     Kuhn A, Loscher D, Marschalek R · Oncotarget 2016
     used by An expression subgroup is not an occupancy subgroup — and this project keeps reading one as the other, HOXB4, the one direct IRX1 target with ChIP evidence, carries no oncoprotein in any of seven infant patients, iALL-IRX1 — the HOXA-negative, IRX1-high state of infant KMT2A::AFF1 ALL, In infant ALL, IRX1 transcript is enriched in KMT2A::AFF1 (21 of 48) and present but rare outside it (3 of 26) - so the occupancy zero outside AFF1 is not an expression zero, IRX1 — Iroquois homeobox 1, the gene that names the HOXA-negative half of infant t(4;11) ALL, IRX1 binds the MLL-AF4 complex non-competitively — menin, LEDGF and DOT1L are all unchanged, IRX1 CUT&RUN in primary t(4;11) blasts — testing Kühn's HEK293T mechanism where it matters, IRX1 fusion occupancy is confined to KMT2A::AFF1: 0 of 18 samples across five other partners, IRX1 is a second address for the KMT2A::AFF1 oncoprotein, not merely the gene that turns HOXA off, Is IRX1 expressed in normal blood at all? Two of the three papers say no, one says exclusively yes, Menin CUT&RUN in an IRX1-high KMT2A::AFF1 blast — the missing track in every public deposit, SEM, the standard t(4;11) model line, has zero signal at IRX1 — every model of this disease is a model of one subgroup, The deposit paper's own supplementary table calls IRX1 an oncoprotein target in exactly p279, p318 and p454 - the same three samples this project reached by a different instrument, The EGR1 promoter fails its own IgG control — an attractive claim withheld because a pre-declared control said no, The IRX1 address requires the AFF1 partner; the menin interface explains the shared HOXA address and not this one
363. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 27050521
     Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes.

     Garcia-Cuellar MP, Büttner C, Bartenhagen C, et al. · Cell Rep 2016
     used by Anti-ENL antibodies are the cleanest partner reagent in this disease and sit on top of the worst confound
364. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 27392123
     Frequency and outcome of pediatric acute lymphoblastic leukemia with ZNF384 gene rearrangements including a novel translocation resulting in an ARID1B/ZNF384 gene fusion

     · Pediatr Blood Cancer 2016
     used by ARID1B (BAF250b) - the cBAF paralogue whose deletion PROMOTES MLL-AF9 leukaemogenesis, which makes it the one gene in this beat whose published KMT2A-fusion result points the wrong way for a drug target
365. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27697924
     ASB7 regulates spindle dynamics and genome integrity by targeting DDA3 for proteasomal degradation.

     Uematsu K, Okumura F, et al. · The Journal of Cell Biology 2016
     used by ASB7 (Q9H672) - the brake on H3K9me3's own positive feedback loop, released by CDK1 in mitosis, and it reached this graph as the flattest dependency in the read queue
366. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27310306
     Collaboration of MLLT1/ENL, Polycomb and ATM for transcription and genome integrity.

     Ui A, et al. · Nucleus 2016
     used by ATM phosphorylates ENL at conserved SQ sites and flips it from elongation to Polycomb repression - on sequence every KMT2A::MLLT1 fusion keeps
367. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27625305
     Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.

     Morgado-Palacin I, Day A, Murga M, Lafarga V, Anton ME, Tubbs A, et al. · Sci Signal 2016
     used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it, If RPA loading at the KMT2A breakpoint cluster region is the licensing step for the etoposide-induced translocation, then the nuclear RPA reserve is a modifier of therapy-related KMT2A-rearranged leukaemia risk - and an ATR inhibitor, which kills by exhausting RPA, would raise that risk rather than lower it, Replication stress and interstrand-crosslink repair as a cell state - an ATR dependency measured in mouse MLL-rearranged AML, and the same stress implicated in breaking the MLL locus in the first place, RPA-coated single-stranded DNA is the structure that licenses ATR: ATRIP reads it, ATR is brought to the lesion, and CHK1 is activated - which is how this corpus's ATR and CHEK1 entries connect to the clamp that had no entry until now, The replication protein A heterotrimer (RPA1/RPA2/RPA3) - the ssDNA clamp that every resection and replication-stress claim in this corpus silently depends on, and which had no entry until cycle 160, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
368. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27723720
     ETAA1 acts at stalled replication forks to maintain genome integrity.

     Bass TE, Luzwick JW, Kavanaugh G, Carroll C, Dungrawala H, Glick GG, Feldkamp MD, Putney R, Chazin WJ, Cortez D · Nat Cell Biol 2016
     used by ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it
369. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27132940
     ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth.

     Atanassov BS, Mohan RD, Lan X, Kuang X, Lu Y, Lin K, McIvor E, Li W, Zhang Y, Florens L, Byrum SD, Mackintosh SG, Calhoun-Davis T, Koutelou E, Wang L, et al. · Mol Cell 2016
     used by ATXN7L3 — the shared adaptor that actually sets H2Bub levels, and a KMT2A-selectivity hit nobody in this field has looked at, Erasing H2Bub: three deubiquitinases share two adaptors, and removing the enzyme the field names lowers the mark instead of raising it, Raise H2Bub in KMT2A-rearranged cells with the existing USP22 macrocycles and see which way the disease moves, USP22 — a KMT2A-rearranged dependency that works through MEIS1 protein stability, and is not an interactor of the fusion
370. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 27647842
     Clinical presentation of childhood leukaemia: a systematic review and meta-analysis.

     Clarke RT, Van den Bruel A, Bankhead C, Mitchell CD, Phillips B, Thompson MJ · Arch Dis Child 2016
     used by Audit of the infant presenting-feature evidence: what exists, what does not, what was rejected, what could not be read, Big liver, big spleen: the organomegaly numbers measured in infants, not pooled from children, Bruising and petechiae: the bleeding signs of thrombocytopenia at presentation, Fever and fatigue: two of the five headline signs cannot be elicited from a baby, Fever and infection: the reason most of these babies see a doctor, and the reason some of them die, Hepatosplenomegaly: the swollen abdomen that is often the first thing a parent notices, Leukaemia cutis: the skin nodules that can be the first sign of infant leukaemia, Pallor and anaemia in infants: the number this graph quotes does not exist for babies, Pallor and fatigue: the anaemia of a marrow taken over by leukaemia, Rash: the one presenting feature that gets commoner the younger the baby is
371. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26766589
     Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia

     Cheung N, Fung TK, Zeisig BB, et al. · Cancer Cell 2016
     used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, Half the KDM4C deposition is not a KMT2A fusion at all: MOZ-TIF2 8, MLL-GAS7 6, MLL-AF9 2, and the human xenograft deposited nothing, KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR, One experiment that decides whether KDM4C is a target or the KDM4 family is: paralogue rescue of SD70 sensitivity in SEM, SFPQ / PSF (P23246) - the last of 21 fusion-construct partners without an entry, and it is itself the 5' half of an ALL fusion that puts ABL1 in the nucleus, The dependencies this project keeps failing to see are the buffered ones: paralogue redundancy and guide placement, not absence of biology, The phase-2 go/no-go register: the numbers we agree to before we look
372. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27563068
     Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes

     Alicea-Velázquez NL, Shinsky SA, Loh DM, Lee JH, Skalnik DG, Cosgrove MS · Journal of Biological Chemistry 2016
     used by Auditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails, SETD1A — a leukemia dependency whose enzyme activity turns out to be dispensable
373. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27568929
     KDM2B recruitment of the Polycomb group complex, PRC1.1, requires cooperation between PCGF1 and BCORL1

     Wong SJ, Gearhart MD, Taylor AB, et al. · Structure 2016
     used by BCOR — the other side of the CBX8 conflict, and a target you would be inhibiting in the direction of disease, BCORL1 — the BCOR paralogue that is in the only crystal structure of the PRC1.1 core, and is the one PRC1.1 subunit nobody has tested in KMT2A-rearranged leukaemia, KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit, PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion, SKP1 — a pan-essential housekeeping adaptor that is also a structural subunit of PRC1.1, which makes it the one PRC1.1 member that can never be a target
374. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     RCSB PDB entry 5JH5 - Structural Basis for the Hierarchical Assembly of the Core of PRC1.1

     · RCSB Protein Data Bank; entry and polymer-entity alignment records queried via data.rcsb.org 2016
     used by BCORL1 — the BCOR paralogue that is in the only crystal structure of the PRC1.1 core, and is the one PRC1.1 subunit nobody has tested in KMT2A-rearranged leukaemia, KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit, PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion, SKP1 — a pan-essential housekeeping adaptor that is also a structural subunit of PRC1.1, which makes it the one PRC1.1 member that can never be a target
375. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27634205
     ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype.

     Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura K, et al., Kiyokawa N · Haematologica 2016
     used by BMP2K (BIKe) - a nuclear serine/threonine kinase, and the ZNF384 fusion partner that is not a chromatin protein, BMP2K::ZNF384 - a PROTEIN KINASE as the 5' partner, with its catalytic domain retained: the counterexample to 'the partner is always a chromatin coactivator', How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, TCF3::ZNF384 - the partner whose contribution is now actually demonstrated: steroid resistance, and it is not shared with EP300::ZNF384, The ZNF384-fusion immunophenotype - weak CD10 with aberrant CD13/CD33 - and the one marker that separates it from KMT2A-rearranged disease runs the OPPOSITE way to expectation
376. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26837759
     Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

     Prieto C, Stam RW, Agraz-Doblas A, Ballerini P, Camos M, Castano J, Marschalek R, Bursen A, Varela I, Bueno C, Menendez P · Cancer Research 2016
     used by Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here, Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL, Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal, KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells, KRAS as a co-mutation in KMT2A-r leukemia — the single most frequently co-mutated gene, and it still cannot start the disease, Measure the RAS allele fraction in CSF blasts and in paired marrow blasts from the same infant on the same day, The RAS-mutant subclone is where the leukaemia goes, not what it is - a dissemination modifier that a marrow aspirate systematically under-counts
377. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.databasePMID 27863956
     IHEC Data Portal metadata API: getReleases.py enumerated 50 releases and getDataHub.py?data_release_id=N pulled every dataset in each, 2026-09-22; assay-label and cell-type tabulation reproducible from the cached hubs

     Bujold D, Morais DAL, Gauthier C, Côté C, Caron M, Kwan T, Chen KC, Laperle J, Markovits AN, Pastinen T, Caron B, Veilleux A, Jacques PÉ, Bourque G · Cell Systems 3:496-499.e2 (the IHEC Data Portal) 2016
     used by Bounded, with every archive named: H3K9me1 and H3K9me2 in a CD34+ progenitor are absent from BLUEPRINT, EGA, Roadmap/Human Epigenome Atlas, the IHEC Data Portal and ENCODE - 49,663 IHEC datasets carry 178 assay labels and H3K9me2 is not one of them - and the absence is a consortium artefact, because GEO has had the CD34+ H3K9me2 data since 2017
378. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     BLUEPRINT Data Coordination Centre, current_release/homo_sapiens/20160816.data.index (9.3 MB, 11,278 file rows), retrieved 2026-09-22 from the EMBL-EBI public FTP over HTTPS

     · BLUEPRINT Epigenome Project / EMBL-EBI 2016
     used by Bounded, with every archive named: H3K9me1 and H3K9me2 in a CD34+ progenitor are absent from BLUEPRINT, EGA, Roadmap/Human Epigenome Atlas, the IHEC Data Portal and ENCODE - 49,663 IHEC datasets carry 178 assay labels and H3K9me2 is not one of them - and the absence is a consortium artefact, because GEO has had the CD34+ H3K9me2 data since 2017
379. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26645404
     Metabolism and disposition of the DOT1L inhibitor, pinometostat (EPZ-5676), in rat, dog and human.

     Waters NJ, Smith SA, Olhava EJ, Duncan KW, et al. · Cancer Chemother Pharmacol 2016
     used by Bounding an absence the graph already asserts: the H3K79me2 decay half-life, counted, dated and controlled - and why three of the six hits are about the drug's half-life, Pinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field
380. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26641009
     Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia.

     Churpek JE, Marquez R, Neistadt B, Claussen K, Lee MK, et al. · Cancer 2016
     used by BRCA1 (P38398, 1,863 aa) - named in 19 entries of this graph and never written: the HR mediator that CTCF and the H3K9 machinery are now reported to license at a break, and the only cascade member with a human therapy-related-leukaemia signal after topoisomerase II therapy, Giving a G9a/GLP inhibitor alongside etoposide or doxorubicin removes a DNA-repair licence at the moment TOP2 breaks are being made - and the sibling compound UNC-0638 is measured to block BRCA1/BARD1 arrival at a break, in children on curative therapy
381. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27063977
     Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study.

     Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, et al. · Lancet Haematology 2016
     used by BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing
382. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27376689
     Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition

     Hohmann AF, Martin LJ, Minder JL, Roe JS, Shi J, Steurer S, Bader G, McConnell D, Pearson M, Gerstberger T, Gottschamel T, Thompson D, Suzuki Y, Koegl M, Vakoc CR · Nature Chemical Biology 12(9):672-9 2016
     used by BRD9 — dispensable in the average cell, rank 39 of 17,728 in KMT2A-rearranged lines, and with an on-target proof most epigenetic targets never get, Is MYC the node? Two papers, the same MLL-AF9 model, opposite answers - and the second one failed to rescue, Separate ncBAF from canonical BAF in KMT2A-rearranged cells: paired degron, paralogue-pair CRISPR, and complex-resolved CUT&RUN
383. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27746112
     Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.

     Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, Bredius RG, Egberts AC, et al. · The Lancet Haematology 2016
     used by Busulfan - the alkylating agent that replaces radiation in infant conditioning, and whose labelled paediatric target range is below the range the modern trial data support
384. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 27799912
     Understanding Mechanisms of GLI-Mediated Transcription during Craniofacial Development and Disease Using the Ciliopathic Mutant, talpid(2).

     Chang YT, Chaturvedi P, Schock EN et al · Frontiers in Physiology 2016
     used by C2CD3 - the centriole-elongation regulator fused to KMT2A exon 8 in an MPNST, predicted OUT OF FRAME, and the partner whose RefSeq transcript is 390 residues shorter than UniProt's canonical
385. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 26914337
     Lineage Switch in MLL-Rearranged Infant Leukemia Following CD19-Directed Therapy

     Rayes A, ..., O'Brien MM · Pediatric Blood & Cancer 2016
     used by CD19 - the molecule this disease is treated by, named in 114 entries and written in none of them until now, Reading the same-source counter-evidence: 77 notes adjudicated, and the defect is not the one the metric measures
386. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27855694
     CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling.

     Fang X, Chen C, Xia F, Yu Z, Zhang Y, Zhang F, Gu H, Wan J, et al. · J Hematol Oncol 2016
     used by CD274 (PD-L1) - named in zero entries of this graph until now, a direct MLL1-H3K4me3 target gene in another tissue, and a cell-intrinsic dependency of MLL-AF9 leukaemia-initiating cells
387. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26886422
     CDK13, a Kinase Involved in Pre-mRNA Splicing, Is a Component of the Perinucleolar Compartment.

     Even Y, Escande ML, Fayet C, Genevière AM · PLoS One 2016
     used by CDK13 - rank 171 of 17,728, equally deep in both lineage halves, and essentially unstudied in leukaemia
388. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27099147
     Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.

     Uras IZ, et al. · Blood 2016;127:2890-902 2016
     used by CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true
389. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26728554
     Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a.

     · Genes Dev 2016
     used by CDKN2A - one gene, two reviewed UniProt records with the same primary symbol, and a deletion that is three times rarer here than in the infant leukaemias next door
390. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27916615
     Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia

     Ebinger S, Ozdemir EZ, Ziegenhain C, Tiedt S, Castro Alves C, Grunert M, et al., Jeremias I · Cancer Cell 2016
     used by Cell-state enumeration: 23 queries, what was written, what was rejected and why — including an empirical confirmation that PubMed reads SEM as two journal names, Hypothesis: menin-inhibitor sensitivity falls with cell-cycle exit, so the compartment that causes relapse is the one the drug reaches least — and nobody has sorted by cycle state to check, Quiescence (G0) — the state 15 entries invoke to explain measurable residual disease, defined here for the first time, Sort KMT2A-rearranged blasts by cell-cycle state, then measure menin-inhibitor response — the one-week experiment nobody has run
391. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26908650
     A DNA binding winged helix domain in CAF-1 functions with PCNA to stabilize CAF-1 at replication forks.

     Zhang K, Gao Y, Li J, et al. · Nucleic Acids Research 2016
     used by CHAF1A (CAF-1 p150) - the subunit that reads PCNA and makes histone deposition replication-coupled, and the half of CAF-1 that leukaemia has not looked at
392. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27477910
     DNA Breaks and End Resection Measured Genome-wide by End Sequencing

     Canela A, Sridharan S, Sciascia N, et al. · Molecular cell 2016
     used by Chromatin loop anchors are DNA-break hotspots - and the two papers that established it disagree about why, Experiment: degrade TOP2A and TOP2B separately in a fetal-like human progenitor and map DNA breaks at the KMT2A locus without a poison, What maps a DNA break, and the fact that none of the modern instruments has ever been pointed at KMT2A in a blood progenitor
393. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26541609
     Distinct routes of lineage development reshape the human blood hierarchy across ontogeny

     Notta F, Zandi S, Takayama N, et al., Dror Y, Dick JE · Science 2016
     used by Common myeloid progenitor (CMP) — the fork at which KMT2A leukaemia almost always turns one way, Retained fetal programme — the infant-versus-adult stem cell difference, and the reason KMT2A::AFF1 needs no second mutation
394. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27154821
     ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia.

     Zhu L, Li Q, et al. · Cancer Discov 2016
     used by CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, Degrade one CXXC reader, ChIP the fusion: the one experiment that settles whether the address is contested, Does the fusion need the PWWP arm? An artificial CXXC + H3K36me2-reader + AF4-interaction protein substitutes for a whole MLL fusion - but LEDGF itself is not required for the fusion to reach chromatin, H3K36me2/3 - the mark that physically switches PRC2 off, that LEDGF reads to reach chromatin, and that a comparator fusion uses to keep EZH2 off HOXA, Hypothesis: LEDGF licenses elongation at fusion target genes rather than anchoring the fusion, which predicts that a LEDGF agent is epistatic with BET and CDK9 inhibition and invisible in a fusion-ChIP assay, Is the CpG address a contested resource? On current evidence, no - and the beat that went looking says so, KDM2A - the CXXC reader that antagonises KMT2A leukaemogenesis, and displaces wild-type MLL rather than the fusion, LEDGF does NOT hold the fusion on chromatin: knocking it down INCREASES fusion occupancy, and an IBD-binding-dead fusion still binds its targets, LEDGF occupancy under revumenib: the measurement the graph called missing exists, in one 2025 preprint, and it goes the way the tenfold cooperativity predicts, Menin and LEDGF hold WILD-TYPE KMT2A on chromatin; for the fusion LEDGF is functionally required but positionally dispensable, The experiment that closes the LEDGF hole: doxycycline-inducible PSIP1 knockdown switched on AFTER a human KMT2A::AFF1 xenograft is established, The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential, The LEDGF hole, measured: every published LEDGF-removal experiment removes it BEFORE or AT transformation, and none treats an established leukaemia in an animal, Three routes to one observation: the CUT&RUN panel that says whether menin eviction, H3K36me3 loss or MLL loss takes LEDGF off the fusion's genes, What LEDGF actually does for the fusion: it brings AF4, CDK9, BRD4, P-TEFb and Ser2P Pol II to the target gene, and H4K16ac with them, What the Polycomb beat searched, what it counted as absent, what it read and rejected, and the two absences it got wrong before hand-back
395. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26774490
     Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration.

     Jin SG, Zhang ZM, et al. · Cell Rep 2016
     used by CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, Is the CpG address a contested resource? On current evidence, no - and the beat that went looking says so, TET3 - the CXXC reader whose domain prefers 5-carboxylcytosine, and the only CXXC-family gene ever found mutated in a KMT2A-rearranged cohort
396. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 27705803
     A High-Density Map for Navigating the Human Polycomb Complexome

     Hauri S, ..., Beisel C · Cell Reports 2016
     used by CSNK2A2 - CK2's other catalytic subunit, expressed in every KMT2A-rearranged line and, if anything, slightly favourable to lose, OGT - the O-GlcNAc transferase, a Polycomb-complexome bait that pulls down KMT2A, and already the metabolic dial on DOT1L in this graph
397. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27520958
     Ctr9, a Key Component of the Paf1 Complex, Affects Proliferation and Terminal Differentiation in the Developing Drosophila Nervous System.

     · G3 (Bethesda) 2016
     used by CTR9 — a PAF1C subunit the field assumes is a fusion partner, with no paper that tested it
398. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27018596
     MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis

     Yokoyama T, Nakatake M, Kuwata T, et al. · J Clin Invest 2016
     used by CXCR4 - named in eighteen entries of this graph with no entry of its own, and the one niche molecule with a drug, a paediatric trial and a direct KMT2A-r experiment, CXCR4 function in KMT2A-rearranged blasts is an output of the fusion's own HOXA/MEIS1 program, so a menin inhibitor should switch off the niche axis without a CXCR4 antagonist, Nobody has reported what a menin inhibitor does to CXCR4: zero papers name menin and CXCR4 together, and the RNA-seq that would answer it is already public, Planned: read CXCR4 and SYTL1 out of the menin-inhibitor transcriptomes that are already public, in the same contrast that shows HOXA9 and MEIS1 falling
399. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 27391351
     FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia.

     Català A, Pastor-Anglada M, Caviedes-Cárdenas L, Malatesta R, Rives S, Vega-García N, et al. · Oncotarget 2016
     used by Cytarabine - the one conventional drug KMT2A-rearranged infant ALL is MORE sensitive to, and the only case in this beat where a mechanism changed a protocol
400. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 26773061
     New players in heterochromatin silencing: histone variant H3.3 and the ATRX/DAXX chaperone

     Voon HP, Wong LH · Nucleic Acids Research 2016
     used by DAXX - the strongest of five selective dependencies among 254 unwritten interactors but it FAILS Bonferroni correction (p=0.0128, rank 4 of 254), and not one paper connects it to this disease
401. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27679741
     DDX6 transfers P-TEFb kinase to the AF4/AF4N (AFF1) super elongation complex.

     Muck F, Bracharz S, Marschalek R · Am J Blood Res 2016
     used by DDX6 - the only protein ever proposed to do for a cell what Tat does for the virus, on the strength of one 2016 paper, Directed extraction of P-TEFb from the reservoir: HIV-1 Tat is the worked example, and the only cellular candidate rests on one unreplicated paper, The two t(4;11) products split AFF1 exactly at the P-TEFb-binding module, and the elongation half goes to the reciprocal
402. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27114368
     Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway.

     Saito S, et al. · Molecular and Cellular Biology 2016
     used by DEK::NUP214 is the sixth lesion on the XPO1 address - and the only one where the drug response was measured in primary patient cells, Where SET::NUP214 actually is: mobile intranuclear bodies that trap CRM1, dissolve in mitosis and under CRM1 inhibitor, and reassemble on washout
403. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26740045
     Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes.

     Oka M, Mura S, Yamada K, et al. · eLife 2016
     used by Docking onto pre-bound XPO1 is a general route to leukaemic chromatin, used by at least seven different lesions - not three coincidences, Two pools of one protein: the chromatin-bound XPO1 that matters here has never been separated biochemically from the soluble export machine
404. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27647347
     Dpy30 is critical for maintaining the identity and function of adult hematopoietic stem cells.

     Yang Z, Shah K, Khodadadi-Jamayran A, Jiang H · Journal of Experimental Medicine 2016
     used by DPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency, DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose, The leukaemia term hid the answer for DPY30 — a rule-77 demonstration with clean rule-67 controls
405. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27019113
     Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults

     Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F, Kojima S, Ueno T, Imoto N, Kohsaka S, Kunita A, Doi K, Sakura T, Yujiri T, Kondo E, Fujimaki K, Ueda Y, Aoyama Y, Ohtake S, Takita J, Sai E, Taniwaki M, Kurokawa M, Morishita S, Fukayama M, Kiyoi H, Miyazaki Y, Naoe T, Mano H · Nat Genet 2016
     used by DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus
406. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27265895
     Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia

     Lilljebjorn H, Henningsson R, Hyrenius-Wittsten A, Olsson L, Orsmark-Pietras C, von Palffy S, Askmyr M, Rissler M, Schrappe M, Cario G, Castor A, Pronk CJH, Behrendtz M, Mitelman F, Johansson B, Paulsson K, Andersson AK, Fontes M, Fioretos T · Nat Commun 2016
     used by DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus, Mechanism class 5 — enhancer hijacking (inv(3) GATA2/EVI1 — and DUX4-r, which only half belongs here), Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents
407. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27776115
     Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

     Zhang J, McCastlain K, Yoshihara H, Xu B, Chang Y, Churchman ML, Wu G, Li Y, Wei L, Iacobucci I, Liu Y, Qu C, Wen J, Edmonson M, Payne-Turner D, Kaufmann KB, Takayanagi SI, Wienholds E, Waanders E, Ntziachristos P, Bakogianni S, Wang J, Aifantis I, Roberts KG, et al., Downing JR, Mullighan CG · Nat Genet 2016
     used by DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus, ERG - a heptad stem-cell transcription factor whose 15 mentions in this graph are mostly about OTHER diseases, and whose best-established role in B-ALL is loss of function, not cooperation, Mechanism class 5 — enhancer hijacking (inv(3) GATA2/EVI1 — and DUX4-r, which only half belongs here)
408. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25893291
     The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia

     Giotopoulos G, Chan WI, Horton SJ, Ruau D, Gallipoli P, Fowler A, Crawley C, Papaemmanuil E, Campbell PJ, Gottgens B, Van Deursen JM, Cole PA, Huntly BJP · Oncogene 35(3):279-89 2016
     used by EP300 — the acetyltransferase whose paralogue split is the finding: p300 is the 108th most KMT2A-selective gene, CBP is the 16,950th
409. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26974126
     Molecular basis and specificity of H2A.Z-H2B recognition and deposition by the histone chaperone YL1.

     Latrick CM, Marek M, Ouararhni K, et al. · Nature Structural & Molecular Biology 2016
     used by EP400 - the ATPase that swaps H2A.Z in; its complex is required by MLL leukaemia stem cells, and in DepMap it is one of the three genes LEAST required in KMT2A-rearranged lines, H2AZ1 - the one histone variant with a direct KMT2A-fusion paper: MLL-AF10 and MLL-ENL recruit Tip60 to Hoxa9 to acetylate H2A.Z, SRCAP - the other H2A.Z-loading motor, whose entire PubMed intersection with MLL is five neurodevelopmental gene panels
410. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27153538
     The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation.

     Jacquet K, Fradet-Turcotte A, Avvakumov N, Lambert JP, et al. · Mol Cell 2016
     used by EPC1 - the NuA4/TIP60 subunit whose C-terminal fragment grips MBTD1, making it the contact a leukaemic fusion cannot do without and the mildest dependency in that whole complex, H4K20me1 - the transcription- and replication-linked H4 state, whose gene-body level tracks Pol II; it HAS been profiled genome-wide in human haematopoietic stem cells twice, and a query scoped to 'leukemia' cannot see either dataset, MBTD1 - the H4K20me1/me2 reader inside NuA4/TIP60, the quiescence brake on adult haematopoietic stem cells, and the 3' partner of ZMYND11::MBTD1 whose methyl-lysine cage the fusion carries and does not use, ZMYND11::MBTD1 is the KMT2A-fusion architecture assembled from different parts - and the part it throws away is a direct physical brake on KMT2A itself
411. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27863249
     Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters

     Javierre BM, Burren OS, Wilder SP, et al. · Cell 2016
     used by Experiment: measure KMT2A-AFF1 spatial proximity in the human fetal progenitor, in the cell and at the time the translocation actually happens
412. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27846391
     Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia

     Lin S, Luo RT, Ptasinska A, Kerry J, Assi SA, Wunderlich M, Imamura T, Kaberlein JJ, Rayes A, Althoff MJ, Anastasi J, O'Brien MM, Meetei AR, Milne TA, Bonifer C, Mulloy JC, Thirman MJ · Cancer Cell 2016
     used by Experiment: where do KMT2A::AFF1 blasts go when a menin inhibitor releases the block? Single-cell lineage destination under drug, Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL, Hypothesis: releasing the KMT2A::AFF1 differentiation block sends cells toward myeloid, not mature B, in a measurable fraction of infant cases, MLL fused to MURINE Af4 in human CD34+ cells — the model that works, and the swap that makes it work, Pre-B cell — the stage KMT2A::AFF1 leukaemia never reaches, and why that boundary is informative, Pro-B cell — the stage at which KMT2A::AFF1 leukaemia is arrested, and the phenotype the diagnosis is made on, The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here, The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there
413. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27216501
     The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication

     Lopez AP, Kugelman JR, Garcia-Rivera J, Urias E, Salinas SA, Fernandez-Zapico ME, Llano M · Journal of Molecular Biology 428(14):2814-31 2016
     used by FACT (SPT16-SSRP1) - the chromatin arm of transcription elongation, and a clean negative result for the KMT2A::AFF1 interactome, SSRP1 - the small FACT subunit, and the only protein in this beat that binds a confirmed KMT2A-fusion interactor directly (LEDGF/p75, via HMG box to PWWP)
414. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26944543
     Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin.

     Man N, Sun XJ, Tan Y, García-Cao M, Liu F, Cheng G, et al. · Blood 2016
     used by Fetal-restricted permissive factors across fusion families - the class has exactly ONE fully worked member, and for ETV6::RUNX1 the fetal advantage is real but no factor is named, ID1 - the only OTHER named factor whose requirement for a KMT2A fusion depends on cell of origin: needed in fetal-liver-derived MLL-AF9 leukaemia, actively restraining in bone-marrow-derived, The fetal state is PERMISSIVE for lymphoid KMT2A-fusion transformation and PROTECTIVE against myeloid - which is why LIN28B has opposite signs in the two literatures
415. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27889185
     NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis

     Xu H, et al. · Cancer Cell 30(6):863-878 2016
     used by Five KMT2A-free NUP98 fusions bind MLL1 and the NSL complex — and one unbiased mass-spectrometry study failed to reproduce it, Interactome round 5: 42 queries, 13 entries written, 9 candidates rejected with counts, and four alias failures of four different kinds, KANSL1 - the NSL scaffold, and the protein through which WDR5 binding to NSL and to MLL/COMPASS is mutually exclusive, NSL complex - the MOF assembly that five NUP98 fusions bind alongside MLL1, and that competes with MLL/COMPASS for WDR5, NUP98::HOXA9, t(7;11)(p15;p15) — the founding NUP98 fusion, and an incomplete oncogene, NUP98::HOXD13, t(2;11)(q31;p15) — the myelodysplasia fusion, and a warning against targeting p53, Verdict on the WRAD contradiction: the graph is right, its citation class is wrong, and its universal is wrong, WDR5 is partitioned, not shared: NSL and SET1/MLL complexes compete for one pool, so perturbing NSL changes how much WDR5 reaches the wild-type KMT2A complex the fusion depends on, WRAD reaches KMT2A fusions only as a passenger on a recruited wild-type complex
416. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 26920889
     A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study

     Cooper TM, Cassar J, Eckroth E, Malvar J, Sposto R, Gaynon P, Chang BH, Gore L, August K, Pollard JA, DuBois SG, Silverman LB, Oesterheld J, Gammon G, Magoon D, Annesley C, Brown PA · Clinical Cancer Research 2016
     used by FLT3 / CD135 — the strongest non-tether co-dependency, and a target the field may have written off on a badly executed trial
417. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27730210
     Maintenance of leukemic cell identity by the activity of the Polycomb complex PRC1 in mice.

     Rossi A, Ferrari KJ, Piunti A, Jammula S, Chiacchiera F, Mazzarella L, et al. · Sci Adv 2016
     used by H2AK119ub - the mark every PRC1.1 claim in this graph rests on, named in fifteen entries and written in none until now, PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion, Prime, wash, divide, rechallenge - the one experiment that would turn 'DOT1L provides transcriptional memory' into a measurement, and it doubles as a dosing-schedule study, RING1 (RING1A) - the paralogue that is not RING1B, and the reason a substring search for 'RING1' in this graph returns the wrong gene, RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once
418. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27337104
     Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases.

     Walport LJ, Hopkinson RJ, Chowdhury R, Schiller R, et al. · Nat Commun 2016
     used by H3R2me2a - the asymmetric arginine mark two residues from H3K4 that LOCKS the WRAD module off the histone tail, and the first arginine mark node in this graph
419. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     Targeting epigenetic networks mediated by Prmt1 and Kdm4c in acute myeloid leukemia (E-MTAB-3322)

     ArrayExpress submitters · EMBL-EBI ArrayExpress / BioStudies 2016
     used by Half the KDM4C deposition is not a KMT2A fusion at all: MOZ-TIF2 8, MLL-GAS7 6, MLL-AF9 2, and the human xenograft deposited nothing
420. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27507877
     Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia.

     Alexander TB, Lacayo NJ, Choi JK, et al. · Journal of Clinical Oncology 2016
     used by Has anyone tested an XPO1 inhibitor in a KMT2A-rearranged system? Yes - four preclinical studies and zero clinical ones, counted with the queries and the controls, Selinexor (XPO1 inhibition) — a real paediatric response rate attached to an unproven mechanism in KMT2A-rearranged disease, Two reasons XPO1 is a hard target: every cell needs it, and blocking it switches on a survival pathway, XPO1 mRNA goes UP when you inhibit the protein - the pharmacodynamic marker that made the paediatric trial interpretable, and what it cannot tell you
421. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27117189
     The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules.

     Zhang W, Aubert A, Gomez de Segura JM, Karuppasamy M, Basu S, et al. · Journal of Molecular Biology 2016
     used by HDAC1 and HDAC2 belong to at least five different corepressor complexes, so an HDAC1/2 observation names no complex - and this graph carried both enzymes without the scaffolds that would tell them apart, MBD3 (O95983) - the methyl-CpG-binding subunit that does NOT bind methylated DNA, and a validated KMT2A::AFF1-selective CRISPR vulnerability that is absent from every column of the pan-fusion interactome, MLL fusions engage NuRD's remodelling arm without its deacetylase arm - and if so, every 'NuRD is repressive' inference in this graph is pointing the wrong way, The MLL-fusion interactome recovers corepressor SCAFFOLDS and not their HDAC1/2 catalytic core: NuRD splits 5/7 remodelling arm versus 0/7 deacetylase arm (Fisher p = 0.021), and HDAC1, HDAC2, RBBP4 and RBBP7 are absent from all seven baits, The NuRD complex - two separable modules, three paralogue choices that change what it does, and a graph that carried its ATPase and its shared core but never the scaffolds that make it NuRD
422. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27810920
     In vivo conditional deletion of HDAC7 reveals its requirement to establish proper B lymphocyte identity and development.

     Azagra A, Román-González L, Collazo O, Rodríguez-Ubreva J, de Yébenes VG, Barneda-Zahonero B, Rodríguez J, Castro de Moura M, Grego-Bessa J, Fernández-Duran I, Islam AB, Esteller M, Ramiro AR, Ballestar E, Parra M · J Exp Med 2016
     used by HDAC7 - the eraser the index fusion silences, where the proposed therapy is to INDUCE the HDAC, and two 2024-2025 papers point in opposite directions
423. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 27246212
     Visualization of HDAC9 Spatiotemporal Subcellular Localization in Primary Neuron Cultures.

     Sugo N, Yamamoto N · Methods Mol Biol 2016
     used by HDAC9 - the only HDAC with a KMT2A-rearrangement expression signature across 211 paediatric patients, and it is high, prognostic, and independent of partner and lineage
424. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26148704
     HEXIM1 induction is mechanistically involved in mediating anti-AML activity of BET protein bromodomain antagonist.

     Devaraj SG, Fiskus W, Shah B, Qi J, Sun B, Iyer SP, Sharma S, Bradner JE, Bhalla KN · Leukemia 2016
     used by HEXIM1 - the brake pad, the only part of the reservoir anyone has deliberately raised in a KMT2A-rearranged cell, and the result was that the leukaemia grew less, HEXIM2 - the paralogue that holds the bound P-TEFb pool constant when HEXIM1 is removed, which is why single-gene experiments on this axis read flat, Measure the free-versus-7SK-bound P-TEFb split in KMT2A::AFF1 cells - the experiment this whole beat turns on, which has never been done, Raising HEXIM1 to brake the fusion's output without touching the fusion - one supporting experiment, one chemical series, and no therapeutic window, The brake pad is actively thinned: autophagy degrades HEXIM1 in MLL-fusion and NPM1c AML cells
425. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27732946
     Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells.

     Huang M, Garcia JS, Thomas D, Zhu L, Nguyen LX, Chan SM, Majeti R, Medeiros BC, Mitchell BS · Oncotarget 2016
     used by HEXIM1 - the brake pad, the only part of the reservoir anyone has deliberately raised in a KMT2A-rearranged cell, and the result was that the leukaemia grew less, KMT2A::AFF1 cells run with more free P-TEFb than other leukaemias - and if they do not, this graph's CDK9 story is about recruitment only, The brake pad is actively thinned: autophagy degrades HEXIM1 in MLL-fusion and NPM1c AML cells
426. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27146823
     PU.1 controls the expression of long noncoding RNA HOTAIRM1 during granulocytic differentiation

     Wei S, Zhao M, Wang X, Li Y, Wang K · Journal of Hematology & Oncology 9(1):44 2016
     used by HOTAIRM1 lncRNA — the myeloid-differentiation transcript at the 3' end of HOXA, with a KMT2A-r evidence gap
427. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27535106
     Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia

     Kuhn MWM, Song E, Feng Z, et al. · Cancer Discovery 2016
     used by Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion, NPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication, NUP98 fusions share the menin dependency (confirmed preclinically) — and the partner-supplied reader/writer module is not why
428. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26612825
     Distinct expression patterns for type II topoisomerases IIA and IIB in the early foetal human telencephalon.

     Harkin LF, Gerrelli D, Gold Diaz DC, Santos C, Alzu'bi A, Austin CA, et al. · J Anat 2016
     used by Hypothesis: what breaks KMT2A in a fetus is TOP2B doing its normal transcription-coupled job in a non-cycling progenitor, with no poison involved and repair capacity as the rate-limiting variable, TOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically
429. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27257215
     Jmjd2/Kdm4 demethylases are required for expression of Il3ra and survival of acute myeloid leukemia cells.

     Agger K, ..., Helin K · Genes Dev 2016
     used by IL3RA / CD123 - not just a myeloid target: the quartile of CD123 expression that carries the KMT2A rearrangements is the quartile that dies
430. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27564129
     TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription

     Okuda H, Takahashi S, Takaori-Kondo A, Yokoyama A · Cell Cycle 15(20):2712-22 2016
     used by Interactome round 4: what was counted, what was written, what was rejected, and the two alias traps this beat fell into and caught, KMT2A-rearranged cells need the factors retained through elongation MORE and the factors ejected at pause release LESS — a six-gene asymmetry nobody has reported, Measure the pausing index at KMT2A::AFF1 target genes — the one number the whole pausing argument turns on, and it has never been reported, SUPT5H (SPT5) — the pausing factor the KMT2A field has never studied, and the counted absence that undercuts 'the fusion hijacks pause release'
431. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26878175
     MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C.

     Zhu N; Chen M; Eng R; DeJong J; Sinha AU; Rahnamay NF; et al. · J Clin Invest 2016
     used by JMJD1C / KDM3C - named in three entries of this graph as one of the only loci that loses fusion occupancy under a menin inhibitor, ranked 23rd of 17,728 for KMT2A-selective dependency in this project's own scan, with the strongest published shRNA effect in SEM - and no entry until now
432. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27796307
     KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification.

     Fournier M, Orpinell M, Grauffel C, Scheer E, Garnier JM, Ye T, Chavant V, Joint M, Esashi F, Dejaegere A, Gönczy P, Tora L · Nat Commun 2016
     used by KAT2A / GCN5 - the SAGA catalytic subunit that reaches this disease through its complex rather than through its own symbol, and whose only chemical tool degrades its paralogue too
433. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27768893
     MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria.

     Chatterjee A, Seyfferth J, Lucci J, Gilsbach R, Preissl S, Bottinger L, Martensson CU, Panhale A, Stehle T, Kretz O, Sahyoun AH, Avilov S · Cell 2016
     used by KAT8/MOF is not only a chromatin enzyme: a measured mitochondrial pool binds mtDNA, and the chromatin address depends on which complex it is in
434. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27107742
     Sam68 affects cell proliferation and apoptosis of human adult T-acute lymphoblastic leukemia cells via AKT/mTOR signal pathway

     Wang Q, et al. · Leuk Res 2016
     used by KHDRBS1 (Sam68) — an RNA-binding protein that holds the MLL-AF4 message DOWN, a class no dropout screen can find
435. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 27698462
     Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.

     Trentin L, Bresolin S, Giarin E, et al. · Sci Rep 2016
     used by Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal
436. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 27282883
     Molecular characterization of KMT2A fusion partner genes in 13 cases of pediatric leukemia with complex or cryptic karyotypes

     Ney Garcia DR, de Souza MT, de Figueiredo AF, et al. · Hematological Oncology 2016
     used by KMT2A intron 9 / exon 9 breakpoints (BCR subregion A): the HOXA-high, older-patient break
437. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27396339
     Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.

     Barrett NA, Malouf C, et al. · Cell reports 2016
     used by KMT2A::AFF1 needs a developmental window and a lymphoid-committed cell — the cell type is a condition of transformation, not a consequence of it, Mll-AF4 mouse genetics — B-lineage tumours, long latency, and never infant pro-B ALL
438. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27812132
     The Human Mixed Lineage Leukemia 5 (MLL5), a Sequentially and Structurally Divergent SET Domain-Containing Protein with No Intrinsic Catalytic Activity.

     Mas-Y-Mas S, Barbon M, Teyssier C, et al. · PLoS One 2016
     used by KMT2E (MLL5) - the family member with a dead SET domain, and the exclusion from COMPASS is justified, When a family shares a complex, the result is family-selective, not member-selective - the protein version of this graph's inhibitor-class rule
439. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26721387
     Hepatoma-derived growth factor-related protein 2 promotes DNA repair by homologous recombination.

     Baude A, Aaes TL, et al. · Nucleic Acids Res 2016
     used by LEDGF PWWP chemistry exists after all - 68 fragment hits, double-digit micromolar leads - and the pocket has a structural ceiling the NSD PWWPs do not, RBBP8 / CtIP - the only unwritten core-complex partner with a DIRECT-interaction record, and the graph already held its mechanism without holding the protein, The bite-back surface: LEDGF tethers CtIP to active chromatin and is required for DNA-end resection and homologous recombination, The paralogue that covers for LEDGF: HRP-2 carries the only other IBD in the human proteome, substitutes for LEDGF in HIV integration, and the double knockout is embryonic lethal
440. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27401346
     Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis.

     Rowe RG, Wang LD, Coma S, Han A, Mathieu R, Pearson DS, Ross S, Sousa P, Nguyen PT, Rodriguez A, Wagers AJ, Daley GQ · J Exp Med 2016
     used by let-7 microRNA family (12 HGNC loci) - the effector LIN28B blocks. CORRECTED IN-SESSION: the headline 'zero papers in KMT2A leukaemia' was a NAME-LIST ARTEFACT; searching MLL instead of KMT2A returns three, one of them directly on point, LIN28B has two routes - blocking let-7, and binding mRNAs directly - and in KMT2A::AFF1 every published mechanism is the direct-mRNA one (let-7 IS measured in mouse MLL-fusion AML: in-session correction), LIN28B-dependent fetal B- and NK-lymphopoiesis - the NORMAL state the leukaemia requirement is parasitic on, and the reason the therapeutic window is narrow by construction
441. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27007052
     Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia.

     Chen L, Sun Y, Wang J, Jiang H, Muntean AG · Oncotarget 2016
     used by let-7 microRNA family (12 HGNC loci) - the effector LIN28B blocks. CORRECTED IN-SESSION: the headline 'zero papers in KMT2A leukaemia' was a NAME-LIST ARTEFACT; searching MLL instead of KMT2A returns three, one of them directly on point, LIN28B has two routes - blocking let-7, and binding mRNAs directly - and in KMT2A::AFF1 every published mechanism is the direct-mRNA one (let-7 IS measured in mouse MLL-fusion AML: in-session correction), PROPOSED: measure let-7 and restore it in the human fetal-liver KMT2A::AFF1 model - an axis measured in mouse MLL-fusion AML but never in the index fusion
442. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27268298
     Lineage switch with t(6;11)(q27;q23) from T-cell lymphoblastic lymphoma to acute monoblastic leukemia at relapse.

     Higuchi Y, Tokunaga K, Watanabe Y, et al. · Cancer Genet 2016
     used by Lineage switch as a menin-inhibitor escape route — documented in a patient on revumenib, and invisible to every resistance-mutation screen, Six relapses and a change of lineage: KMT2A::AFDN T-lymphoblastic lymphoma that came back as monoblastic leukaemia, and a seventh remission that held
443. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27460500
     CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

     Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, et al. · Nature Communications 2016
     used by Lineage switch in KMT2A-rearranged leukemia — the same clone changes what kind of blood cell it is
444. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26608508
     Recurrent translocation t(10;17)(p15;q21) in minimally differentiated acute myeloid leukemia results in ZMYND11/MBTD1 fusion

     de Rooij JD, van den Heuvel-Eibrink MM, Kollen WJ, et al. · Genes, Chromosomes & Cancer 2016
     used by MBTD1 - the H4K20me1/me2 reader inside NuA4/TIP60, the quiescence brake on adult haematopoietic stem cells, and the 3' partner of ZMYND11::MBTD1 whose methyl-lysine cage the fusion carries and does not use, ZMYND11::MBTD1, t(10;17)(p15;q21) - a chromatin reader welded to the NuA4/TIP60 acetyltransferase, maintaining Hoxa/Meis1/Myb/Myc/Sox4 in AML: the KMT2A-fusion architecture built from different parts
445. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27744293
     Regulation of DNA replication and chromosomal polyploidy by the MLL-WDR5-RBBP5 methyltransferases.

     Lu F, Wu X, Yin F, Chia-Fang Lee C, et al. · Biol Open 2016
     used by MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7
446. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27068464
     BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements

     · PubMed record; title and year read from the esummary response for this PMID on 2026-09-19. Authors, journal and DOI were NOT fetched in this session and are deliberately omitted rather than written from recall. 2016
     used by MED12 - a named menin-associated protein that restrains menin's transcriptional output, and the anchor of the CDK8 module a KMT2A-r AML paper co-targets, MED23 — rank 16 of 17,728, survives the lineage split with the B-lineage half stronger, and is not absent from the leukaemia literature after all, MED23 confirmed, and the zero-record claim corrected: it is not literature-free in leukaemia, an shRNA screen already found it, The Mediator/BET deposition is 48 of 48 mouse MLL-AF9/NrasG12D samples: resolving the KMT2A status behind the MED23 verdict
447. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26084867
     Menin-MLL inhibitors block oncogenic transformation by MLL-fusion proteins in a fusion partner-independent manner.

     He S, Malik B, Borkin D, Miao H, et al. · Leukemia 2016
     used by Menin dependence of KMT2A::MLLT1: real, repeatedly demonstrated, and always as one lane of a partner panel, Menin dependence of KMT2A::MLLT3: the fusion the co-IP was done on, the largest named partner in the pivotal trial, and still no published response rate
448. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27117702
     The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells.

     Lin S; Choe J; Du P; Triboulet R; Gregory RI · Mol Cell 2016
     used by METTL3 — the m6A writer with a clinical-grade inhibitor, an MLL-rearranged AML mechanism, and a B-lymphoid signal that goes the wrong way
449. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26174629
     Aberrant expression of miR-9/9* in myeloid progenitors inhibits neutrophil differentiation by post-transcriptional regulation of ERG

     Nowek K, Sun SM, Bullinger L, Bindels EMJ, Exalto C, Dijkstra MK, van Lom K, Döhner H, Erkeland SJ, Löwenberg B, Jongen-Lavrencic M · Leukemia 30(1):229-37 2016
     used by miR-9 — the most MLL-specific microRNA in AML, encoded at three separate loci nobody has disambiguated
450. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27105114
     Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain.

     Li Y, Sabari BR, Panchenko T, Wen H, Zhao D, Guan H, Wan L, Huang H, Tang Z, Zhao Y, Roeder RG, Shi X, Allis CD, Li H · Mol Cell 2016
     used by MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is
451. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27325891
     Targeting MTHFD2 in acute myeloid leukemia.

     Pikman Y, Puissant A, Alexe G, et al., Stegmaier K · J Exp Med 2016
     used by MTHFD2 (P13995) - the one panel member with a published MLL-AF9 in-vivo survival result, and the serine gene that behaves exactly like an ISR gene
452. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27613868
     The Oncogenic Fusion Proteins SET-Nup214 and Sequestosome-1 (SQSTM1)-Nup214 Form Dynamic Nuclear Bodies and Differentially Affect Nuclear Protein and Poly(A)+ RNA Export.

     Port SA, Mendes A, Valkova C, Spillner C et al. · J Biol Chem 2016
     used by NUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions, Two pools of one protein: the chromatin-bound XPO1 that matters here has never been separated biochemically from the soluble export machine, Where SET::NUP214 actually is: mobile intranuclear bodies that trap CRM1, dissolve in mitosis and under CRM1 inhibitor, and reassemble on washout
453. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26685999
     Formation of Nup98-containing nuclear bodies in HeLa sublines is linked to genomic rearrangements affecting chromosome 11

     Romana S, Radford-Weiss I, Lapierre JM, Doye V, et al. · Chromosoma 2016
     used by NUP98 - the mobile nucleoporin that leaves the pore to put H3K4me3 on haematopoietic promoters, and the shared 5' donor of seven fusions in this graph
454. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26542893
     ETV6-LPXN fusion transcript generated by t(11;12)(q12.1;p13) in a patient with relapsing acute myeloid leukemia with NUP98-HOXA9

     Abe A, et al. · Genes, Chromosomes & Cancer 55(3):242-250 2016
     used by NUP98::HOXA9, t(7;11)(p15;p15) — the founding NUP98 fusion, and an incomplete oncogene
455. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 28249294
     Coexpression of NUP98/TOP1 and TOP1/NUP98 in de novo Acute Myeloid Leukemia with t(11;20)(p15;q12) and t(2;5)(q33;q31)

     Yamamoto K, et al. · Cytogenetic and Genome Research 150(3-4):287-292 2016
     used by NUP98::TOP1, t(11;20)(p15;q11~q12) — the most precisely mapped NUP98 breakpoint, and the reciprocal that was wrong twice
456. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26813358
     Expression and Role of the ErbB3-Binding Protein 1 in Acute Myelogenous Leukemic Cells.

     Nguyen le XT, Zhu L, Lee Y, Ta L, Mitchell BS · Clin Cancer Res 2016
     used by PA2G4 / EBP1 (Q9UQ80) - the best-evidenced member of the MLL-fusion nucleolar block in the index fusion's own column (p = 0.014), and the only one with a published AML phenotype
457. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26369984
     Outcome of relapsed infant acute lymphoblastic leukemia treated on the interfant-99 protocol

     · Leukemia 2016
     used by Papers we know exist, know matter, and cannot read, When infant leukaemia comes back, it comes back early and while treatment is still running
458. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26744420
     A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.

     Starnes LM, Su D, Pikkupeura LM, et al. · Genes Dev 2016
     used by PAXIP1 (PTIP) - the subunit that tells an MLL3/4 complex apart from a menin complex, and the only one with a leukaemic-niche phenotype
459. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26747896
     PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease

     Li Z, Chen P, Su R, Hu C, Li Y, Elkahloun AG, Zuo Z, Gurbuxani S, et al. · Cancer Research 76:619-629 2016
     used by PBX3 - the TALE cofactor the field says is non-redundant, and the experiment that says HOXA9 is the redundant one, The druggable node in the homeodomain code is the MEIS1-PBX3 interface, not the HOX-PBX one - and it is the only one nobody has attacked, The HOX-PBX interface, and its one peptide: HXR9/HTL001 has been tried in eight tumour types and in KMT2A-rearranged leukaemia exactly once, The PBX3-MEIS1 dimer, not HOXA9, is the unit that reproduces the MLL-fusion transcriptome - and it turns the HOXA cluster on from underneath
460. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26748712
     Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis

     van den Boom V, Maat H, Geugien M, Rodriguez Lopez A, Sotoca AM, Jaques J, Brouwers-Vos AZ, Fusetti F, Groen RWJ, Yuan H, Martens ACM, Stunnenberg HG, Vellenga E, Martens JHA, Schuringa JJ · Cell Reports 14(2):332-46 2016
     used by PCGF1 — the PRC1.1 scaffold whose LOSS causes menin-inhibitor resistance, so it is a restraint on the leukaemia rather than a dependency of it, PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion
461. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27588395
     CATS (FAM64A) abnormal expression reduces clonogenicity of hematopoietic cells.

     Barbutti I, Xavier-Ferrucio JM, Machado-Neto JA, Ricon L, Traina F, Bohlander SK, Saad ST, Archangelo LF · Oncotarget 2016
     used by PICALM (CALM) - the clathrin-assembly adaptor that is the 5' partner of CALM::AF10
462. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27149463
     Association Between PIP4K2A Polymorphisms and Acute Lymphoblastic Leukemia Susceptibility.

     Liao F, Yin D, Zhang Y, et al. (9 authors; senior author Li Y) · Medicine (Baltimore) 2016
     used by PIP4K2A - the lipid kinase at a genome-wide childhood-ALL susceptibility locus, whose product is the ligand a PHD finger reads
463. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     A Phase I Study Using Plerixafor as a Chemosensitizing Agent for Relapsed Acute Leukemia and MDS in Pediatric Patients (POETIC; Seattle Children's Hospital, IRB00047475)

     · ClinicalTrials.gov 2016
     used by Plerixafor (AMD3100, Mozobil) - a licensed CXCR4 antagonist that has never been given to an infant with leukaemia, and whose only paediatric efficacy study failed, POE 10-03 / NCT01319864 — the only completed paediatric trial of niche disruption, which mobilised blasts 3.4-fold and produced three responses in nineteen children, none of them in ALL
464. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26847029
     BCOR regulates myeloid cell proliferation and differentiation

     Cao Q, Gearhart MD, Gery S, Shojaee S, Yang H, Sun H, Lin DC, Bai JW, Mead M, Zhao Z, Chen Q, Chien WW, Alkan S, Alpermann T, Haferlach T, Muschen M, Bardwell VJ, Koeffler HP · Leukemia 30(5):1155-65 2016
     used by PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion, RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once
465. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27705745
     RYBP stimulates PRC1 to shape chromatin-based communication between Polycomb repressive complexes.

     Rose NR, King HW, Blackledge NP, Fursova NA, et al. · Elife 2016
     used by PRC1.1 is not both an effector and a resistance gene by coincidence: the two published readings are one activity measured from opposite ends, RYBP - the subunit that makes a variant PRC1 complex catalytically active, named by two entries in this graph and never written, Titrate PRC1.1 capacity against menin-inhibitor response, and measure H2AK119ub on the same timecourse as H3K79me2
466. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27070704
     The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice

     Townsend EC, Murakami MA, Christodoulou A, et al. · Cancer Cell 2016
     used by PRoXe — the one leukaemia xenograft repository that is actually public, and what that buys
467. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26938874
     Role of CTCF in Regulating SLC45A3-ELK4 Chimeric RNA

     Qin F, Song Y, Zhang Y, Facemire L, Frierson H, Li H · PLoS ONE 2016
     used by Read-through (cis-SAGe) chimeras: most 'fusions' called from RNA-seq in childhood ALL are normal conjoined genes
468. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27307493
     Efficient nuclear export of p65-IκBα complexes requires 14-3-3 proteins.

     Aguilera C, et al. · J Cell Sci 2016;129:2472 2016
     used by RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin
469. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26867678
     SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing.

     Chen S, Blank MF, Iyer A, Huang B, Wang L, Grummt I, Voit R · Nat Commun 2016
     used by RRP9 / U3-55K (O43818) - the U3 snoRNP-specific core protein in four MLL-fusion interactomes but NOT the index fusion's, and the block's only member with a published acetylation switch
470. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27068473
     MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis.

     Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K, et al., Marks KM · Cell Rep 2016
     used by SAM / methionine dependence - the one metabolic state in this graph demonstrated in KMT2A-rearranged lymphoblastic leukaemia itself, with a drug and a PDX behind it, The KMT2A-rearranged DepMap arm is not MTAP-deleted, and the gene that looked like the test cannot answer it, The MTAP-deleted, MTA-high state - a genotype-imposed metabolic state that this project's KMT2A-rearranged arm turns out NOT to have, and that its own screen could never have detected directly
471. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26728555
     Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity.

     Luo Z, Lin C, Woodfin AR, Bartom ET, Gao X, Smith ER, Shilatifard A · Genes & Development 2016
     used by SEC-L3 — the AFF3-scaffolded complex, and the only SEC-family member with a known physiological job: genomic imprinting and X inactivation, The shared reader sits in a complex whose only well-defined normal job is parent-of-origin silencing — and the published safety package for YEATS inhibition is entirely haematopoietic
472. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 25956045
     SET-NUP214 rearrangement in isolation is insufficient to induce leukemia: a single center experience.

     Prokopiou C, et al. · Leuk Lymphoma 2016
     used by SET::NUP214 (TAF-Ibeta-NUP214, SET-CAN), cryptic del(9)(q34.11q34.13) - a HOXA-driving fusion of a histone chaperone to a nucleoporin, with no KMT2A and no menin-binding motif, The entire experimental model space for SET::NUP214 is two cell lines, neither of them in DepMap, with no mouse model found - so every mechanism in this beat is n = 1 or n = 2
473. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27301860
     Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes.

     Koide S, Oshima M, Takubo K, Yamazaki S, et al. · Blood 2016
     used by SETDB1 (Q15047, KMT1E/ESET) - the second H3K9me3 writer: it represses the fusion's own targets via the PAF1 complex, it is required in fetal liver HSPCs and in leukaemic stem cells, and it is a broad dependency in half the CRISPR panel - three published directions that do not agree
474. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27029610
     ATRX binds to atypical chromatin domains at the 3' exons of zinc finger genes to preserve H3K9me3 enrichment.

     Valle-Garcia D, Qadeer ZA, McHugh DS, Ghiraldini FG, et al. · Epigenetics 2016
     used by SETDB1 (Q15047, KMT1E/ESET) - the second H3K9me3 writer: it represses the fusion's own targets via the PAF1 complex, it is required in fetal liver HSPCs and in leukaemic stem cells, and it is a broad dependency in half the CRISPR panel - three published directions that do not agree
475. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26929412
     Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase.

     Fu W, Liu N, et al. · J Biol Chem 2016
     used by SMYD3 - a lysine methyltransferase with three claimed histone marks and one robust non-histone substrate, sitting on an HOXA9 feed-forward loop in MLL-AF9 AML and a fatty-acid-oxidation axis in CML stem cells, with zero interventional trials
476. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27655694
     Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis.

     Bagislar S, Sabò A, et al. · Oncotarget 2016
     used by SMYD3 - a lysine methyltransferase with three claimed histone marks and one robust non-histone substrate, sitting on an HOXA9 feed-forward loop in MLL-AF9 AML and a fatty-acid-oxidation axis in CML stem cells, with zero interventional trials
477. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26985287
     Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor.

     Mitchell LH, Boriack-Sjodin PA, et al. · ACS Med Chem Lett 2016
     used by SMYD3 - a lysine methyltransferase with three claimed histone marks and one robust non-histone substrate, sitting on an HOXA9 feed-forward loop in MLL-AF9 AML and a fatty-acid-oxidation axis in CML stem cells, with zero interventional trials
478. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26990989
     SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.

     Kim JH, Baddoo MC, Park EY, Stone JK, Park H, Butler TW, et al. · Mol Cell 2016
     used by SON (P18583) - a nuclear speckle scaffold that BINDS MENIN and inhibits MLL complex assembly, and the one protein in this tranche the Skucha authors name in their own discussion
479. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26791235
     Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia.

     Huang H, Jiang X, et al. · Cancer Lett 2016
     used by TET1 (LCX / CXXC6) - a CXXC reader that is also a KMT2A fusion partner, and whose leukaemic fusion throws its own CXXC domain away
480. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26878240
     7SK-BAF axis controls pervasive transcription at enhancers

     Flynn RA, Do BT, Rubin AJ, Calo E, Lee B, Kuchelmeister H, Rale M, Chu C, Kool ET, Wysocka J, Khavari PA, Chang HY · Nature Structural & Molecular Biology 23(3):231-8 2016
     used by The 7SK elongation brake is not an off-chromatin reservoir: 7SK occupies enhancers and super-enhancers genome-wide, recruits BAF and repositions nucleosomes - which means NOT APPLICABLE is the wrong epigenetics annotation for LARP7, MEPCE and HEXIM2, and BOUNDED ABSENCE is the right one
481. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27343252
     Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia

     Khaw SL, Suryani S, Evans K, Richmond J, Robbins A, Kurmasheva RT, et al., Lock RB · Blood 2016
     used by The apoptotic priming state — KMT2A-rearranged infant ALL is the one childhood ALL subgroup that is BCL-2-dependent rather than BCL-XL-co-dependent, and BH3 profiling is how that was measured
482. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27666791
     Development Refractoriness of MLL-Rearranged Human B Cell Acute Leukemias to Reprogramming into Pluripotency

     Munoz-Lopez A, Romero-Moya D, Prieto C, Ramos-Mejia V, Agraz-Doblas A, Varela I, Buschbeck M, Palau A, Carvajal-Vergara X, Giorgetti A, Ford A, Lako M, Granada I, Ruiz-Xiville N, Rodriguez-Perales S, Torres-Ruiz R, Stam RW, Fuster JL, Fraga MF, Nakanishi M, Cazzaniga G, Bardini M, Cobo I, Bayon GF, Fernandez AF, Bueno C, Menendez P · Stem Cell Reports 2016
     used by The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia, The pluripotent stem-cell route has failed from both ends, and the failures are informative
483. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.database
     PDB 5SVH: Crystal structure of the KIX domain of CBP in complex with a MLL/c-Myb chimera

     RCSB entry records no primary citation authors; deposition listed as To Be Published · RCSB Protein Data Bank 2016
     used by The KMT2A transactivation domain on the CBP KIX domain: a cooperative allosteric site at 2842-2858, solved three times, and thrown away by every breakpoint
484. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26595813
     PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia

     Cole CB, Verdoni AM, Ketkar S, et al. (Ley TJ, senior author) · Journal of Clinical Investigation 126(1):85-98 2016
     used by The KMT2A-r DNA methylation signature — focal hypermethylation, no global hypomethylation, and a hypomethylating agent that did not help
485. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26729896
     Increased DNA methylation of Dnmt3b targets impairs leukemogenesis

     Schulze I, Rohde C, Scheller-Wendorff M, et al. (Muller-Tidow C, senior author) · Blood 127(12):1575-1586 2016
     used by The KMT2A-r DNA methylation signature — focal hypermethylation, no global hypomethylation, and a hypomethylating agent that did not help
486. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.PMID 26912360
     MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells.

     Kryukov GV, Wilson FH, Ruth JR · Science 2016
     used by The KMT2A-rearranged DepMap arm is not MTAP-deleted, and the gene that looked like the test cannot answer it, The MTAP-deleted, MTA-high state - a genotype-imposed metabolic state that this project's KMT2A-rearranged arm turns out NOT to have, and that its own screen could never have detected directly
487. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     BET inhibition releases the Mediator complex from specific cis elements in acute myeloid leukemia [RNA-seq] (GSE74650)

     GEO submitters · NCBI Gene Expression Omnibus 2016
     used by The Mediator/BET deposition is 48 of 48 mouse MLL-AF9/NrasG12D samples: resolving the KMT2A status behind the MED23 verdict
488. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26912361
     Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5.

     Mavrakis KJ, McDonald ER, Schlabach MR, Billy E, Hoffman GR, deWeck A, et al., Sellers WR · Science 2016
     used by The MTAP-deleted, MTA-high state - a genotype-imposed metabolic state that this project's KMT2A-rearranged arm turns out NOT to have, and that its own screen could never have detected directly
489. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 27708057
     Systematic mapping of functional enhancer-promoter connections with CRISPR interference.

     Fulco CP, Munschauer M, Anyoha R, Munson G, et al. · Science 2016
     used by The noncoding dependency screen five hypotheses in this graph are waiting on - and the KMT2A-rearranged screen that already exists and bounds it
490. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27432891
     Male Men1 heterozygous mice exhibit fasting hyperglycemia in the early stage of MEN1.

     Gao Z, Zhang L, Xie W, Wang S, Bao X, Guo Y, et al. · Journal of Endocrinology 2016
     used by The other half of the islet story: losing menin also costs the beta cell its identity and raises glucagon, Three extra tubes: the glucose study that answers the inversion in children
491. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26681452
     Whole-Exome Sequencing in Nine Monozygotic Discordant Twins.

     Zhang R, Thiele H, Bartmann P et al · Twin Research and Human Genetics 2016
     used by TMPRSS13 (MSPL) - a cell-surface serine protease fused in frame to KMT2A exon 20, the clearest NOT-APPLICABLE epigenetics call of the seven, and a symbol whose approved form has a third of its alias's recall
492. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27582050
     Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders.

     Uusküla-Reimand L, et al. · Genome Biol 2016;17:182 2016
     used by TOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically
493. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27768874
     FANCD2 Facilitates Replication through Common Fragile Sites.

     Madireddy A, Kosiyatrakul ST, et al. · Mol Cell 2016
     used by Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
494. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 27798105
     Effects of the Bowen-Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment.

     Warda AS, Freytag B, Haag S, Sloan KE, Görlich D, Bohnsack MT · Hum Mol Genet 2016
     used by UTP14A (Q9BVJ6) - an SSU processome component that binds and destabilises p53, in four MLL-fusion interactomes but NOT the index fusion's and below the screen threshold
495. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26757981
     De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.

     Lugtenberg D, Reijnders MR, Fenckova M, Bijlsma EK, Bernier R, van Bon BW, Smeets E, Vulto-van Silfhout AT, Bosch D, Eichler EE, Mefford HC, Carvill GL, Bongers EM, Schuurs-Hoeijmakers JH, Ruivenkamp CA, et al. · Eur J Hum Genet 2016
     used by WAC — the adaptor that hands RNF20/RNF40 to RNA polymerase II, and the only member of this axis whose knockdown alone killed MLL-rearranged ALL cells
496. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26886794
     Structural basis for activity regulation of MLL family methyltransferases.

     Li Y, Han J, Zhang Y, et al. · Nature 2016
     used by WDR5 and RBBP5: the second arm of the WRAD hub, RBBP5 V375-D376-V377 into the same propeller face, co-crystallised with the MLL1 WIN peptide in one structure
497. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26989914
     The Effects of Hospital Length of Stay on Readmissions for Children With Newly Diagnosed Acute Lymphoblastic Leukemia

     Wedekind MF, Dennis R, Sturm M, et al. · Journal of Pediatric Hematology/Oncology 2016
     used by What it costs to treat a child through frontline leukemia therapy
498. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26858334
     Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol

     Jacola LM, Krull KR, Pui CH, Pei D, Cheng C, Reddick WE, Conklin HM · Journal of Clinical Oncology 2016
     used by What the treated brain looks like later: neurocognitive late effects after CNS-directed therapy in infancy
499. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 26740869
     Prognostic Impact of WT-1 Gene Expression in Egyptian Children with Acute Lymphoblastic Leukemia

     Hagag AA, Badraia IM, Hassan SM, Abd El-Lateef AE · Mediterr J Hematol Infect Dis 8:e2016008 2016
     used by WT1 - Wilms tumour 1, leukaemia antigen and MRD marker, and the widest-margin promoter in the Q152 AFF1-only core
500. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26883583
     Digital PCR for quantification of recurrent and potentially actionable somatic mutations in circulating free DNA from patients with diffuse large B-cell lymphoma.

     Camus V, Sarafan-Vasseur N, Bohers E, et al. · Leukemia & Lymphoma 2016
     used by XPO1 E571K: a change-of-function hot spot in the NES-binding groove - and it does NOT confer resistance to the drugs that bind the same groove
501. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 27676121
     Determination of local chromatin composition by CasID.

     Schmidtmann E, Anton T, Rombaut P, Herzog F, Leonhardt H · Nucleus 2016
     used by ZNF512 (Q96ME7) - the one protein of the nine deferred pan-MLL-fusion preys that is a sequence-specific chromatin factor, and it initiates pericentric heterochromatin
502. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25281560
     Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.

     Lambert JP, et al. · J Proteomics 2015
     used by A BioID hit is a neighbour, not a complex member - and the two methods are known to disagree, AFF1-NPM1 proximity: nucleophosmin is the only bait in any published proximity experiment whose neighbourhood contains AFF1, KMT2A and menin together, AFF1-RBM15 proximity: the m6A-complex adaptor, itself a paediatric leukaemia fusion partner, has AFF1 in its BioID neighbourhood, Re-adjudicating the standing weak spot: proximity labelling HAS sampled AFF1, KMT2A and five leukaemia fusions - just never a KMT2A fusion, The fusion-oncoprotein TurboID experiment this graph proposes has already been published - for PML::RARA, RUNX1::RUNX1T1, CBFB::MYH11, NUP98::HOXA9 and SET::NUP214, and not for any KMT2A fusion
503. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26424858
     regioneR: an R/Bioconductor package for the association analysis of genomic regions based on permutation tests

     Gel B, Diez-Villanueva A, Serra E, Buschbeck M, Peinado MA, Malinverni R · Bioinformatics 32:289-291 2015
     used by A Jaccard index is not a result until its null knows that active promoters cluster, An activity-stratified permutation null for promoter-set overlap, and the check that its hypergeometric shortcut is not an instrument bug, On one universe with one rule and a structure-respecting null, the two lineages of one infant overlap no more than two unrelated KMT2A::AFF1 infants do
504. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 25962847
     Tumor suppressor Menin acts as a corepressor of LXRα to inhibit hepatic lipogenesis.

     Cheng P, et al. · FEBS Lett 2015
     used by A menin inhibitor is a partial LXR agonist, and no trial in the class has looked, Measure ABCA1, ABCG1 and SREBF1 before and during menin inhibition - a three-transcript panel on samples that already exist, Menin is a corepressor of the LXR sterol sensors - one paper supplies three of this graph's twelve missing partners, and the function has never been written down here, NR1H2 / LXR-beta - the paralogue arm of the menin-LXR contact, present in both species and absent from the paper's conclusion, NR1H3 / LXR-alpha - the best-observed of the three MEN1 sterol partners, with both directions curated in two species, and menin as its corepressor, SREBF1 / SREBP-1 - the weakest of the three MEN1 sterol partners, because it is simultaneously the pathway's readout
505. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26571505
     SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.

     Cruickshank VA, Sroczynska P, Sankar A, Miyagi S, Rundsten CF, Johansen JV, et al. · PLoS One 2015
     used by A time-resolved BRG1/RING1B/H2AK119ub CUT&RUN at BENC under menin inhibition - the inv(16) experiment, run on the right disease, DPF2 (BAF45D) - a cBAF-specific reader required in MLL-AF9 cells, with one PubMed record in this disease and no selectivity signal, Enumeration of candidate cooperating lesions in KMT2A-rearranged leukaemia - what was written, what was recorded as a gap, and what was read and rejected, How BAF maintains KMT2A-rearranged leukaemia: it holds the blast undifferentiated, and it does so in other leukaemias too, Is BENC even on in the disease this project is about? A module-resolved accessibility and deletion map in KMT2A::AFF1 B-lineage cells, Is MYC the node? Two papers, the same MLL-AF9 model, opposite answers - and the second one failed to rescue, Menin inhibition recruits PRC1 to the BENC MYC enhancer cluster and evicts BRG1, exactly as CBFbeta-SMMHC inhibition does in inv(16), Separate ncBAF from canonical BAF in KMT2A-rearranged cells: paired degron, paralogue-pair CRISPR, and complex-resolved CUT&RUN, SMARCA4 (BRG1) - a tumour suppressor by mutation and a maintenance requirement by knockdown, and in KMT2A-rearranged lines the dependency data say it is not selective at all, SMARCD2 (BAF60B) - named in one KMT2A paper in the whole of PubMed, and the dependency it carries is myeloid identity, not the rearrangement, The MYC contradiction can be advanced but not closed: the enhancer is independently validated, the SWI/SNF route is not, and the two papers never measured the same thing, The SWI/SNF dependency in KMT2A-rearranged leukaemia belongs to ncBAF, not to canonical BAF - and the drug in the clinic is aimed at the wrong module
506. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25921540
     Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential.

     Kuntimaddi A, Achille NJ, Thorpe J, Lokken AA, Singh R, Hemenway CS, Adli M, Zeleznik-Le NJ, Bushweller JH · Cell Rep 2015
     used by AFF1 AF4_int motif to AF9/ENL AHD: the index fusion's only documented elongation interface, and it competes with DOT1L, DOT1L — the target where excellent chemistry met an indirect interaction, DOT1L and H3K79 in KMT2A::MLLT3: recruitment is a graded dial that sets methylation and transformation - and the fusion it was discovered in produced no remission in the DOT1L trial, H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of, H3K79me3 - the third methyl group, the one that needs the most enzyme flux and the one human DOT1L makes least of, Import class 2: AHD-dependent mechanism, which cannot transfer because KMT2A::AFF1 has no AHD, KMT2A::AFF1 has no mapped interface to DOT1L: it lacks both structurally defined recruitment modules, and the one complex-level route claimed for it is contested by reconstitution, MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is, Repeat the H3K79 partition in a human KMT2A::AFF1 line: menin inhibition and MLLT10 knockout, side by side with a KMT2A::MLLT3 line, The 2x2 paralogue swap: separate 'is the reader there' from 'which backbone is it on', in one background with matched expression, The KMT2A::MLLT3 chimeric protein: what survives the join on each side, in residue numbers - and the four AF9 modules that do not, The retained AF9 surface in residue detail: one disordered 70-mer, three DOT1L sites, two of them high-affinity and simultaneously occupiable, The transfer rule: which MLL-AF9 results can be carried into t(11;19) and t(4;11), and which are statements about a protein missing a reading module
507. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.trial_registry
     Phase Ib/IIa Study of Palbociclib in MLL-rearranged Acute Leukemias AMLSG 23-14/Palbo-AL-1

     University of Ulm; Pfizer; National Center for Tumor Diseases, Heidelberg · ClinicalTrials.gov 2015
     used by AMLSG 23-14 / Palbo-AL-1 (NCT02310243) — the only trial ever run in MLL-rearranged acute leukemia with a CDK4/6 inhibitor, and it reported nothing, CCND3 (cyclin D3) — the scan's rank-4 hit, and the only one of the four with a drug class already in children, CDK4/6 inhibition in KMT2A-rearranged leukemia — the class was already tried, and the trial never reported
508. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26212453
     An Interactive Database for the Assessment of Histone Antibody Specificity.

     Rothbart SB, Dickson BM, Raab JR, Grzybowski AT, et al. · Mol Cell 2015
     used by An assay that cannot separate me2a from me2s cannot test the arginine switch - the two states are isobaric and predict OPPOSITE things, so a non-discriminating readout returns no information rather than an imprecise answer, H3R2me2a - the asymmetric arginine mark two residues from H3K4 that LOCKS the WRAD module off the histone tail, and the first arginine mark node in this graph
509. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25678665
     A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice

     Illendula A, Pulikkan JA, Zong H, et al. · Science 2015
     used by Analysis (planned) — comparative druggability scan of every obligate fusion-partner interface in the atlas, CBFB::MYH11 (CBFbeta-SMMHC), inv(16)(p13;q22), Experiment (proposed) — cross-family interface point-mutant panel: is the obligate interface real in each fusion?, Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion, Mechanism class 2 — transcription-factor corruption (RUNX1::RUNX1T1, PML::RARA, ETV6::RUNX1, CBFB::MYH11) — a balance, not a pure dominant negative, RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22)
510. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26367798
     Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

     Rathert P, Roth M, Neumann T, et al. (Vakoc CR, Zuber J, senior authors) · Nature 525(7570):543-547 2015
     used by Analysis (runnable): is there a shared cell-state signature behind non-genetic menin-inhibitor and BET-inhibitor resistance?, BENC - the MYC blood enhancer cluster 1.7 Mb downstream, required for MLL-AF9 leukaemia maintenance, and named in zero entries of this graph until now, Experiment: apply all three pressures and ask whether the survivors are the same cell, Hypothesis: the ceiling on menin-interface disruption is cell-state plasticity, not target mutation, The MYC contradiction can be advanced but not closed: the enhancer is independently validated, the SWI/SNF route is not, and the two papers never measured the same thing, Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
511. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26367796
     BET inhibitor resistance emerges from leukaemia stem cells

     Fong CY, Gilan O, Lam EYN, et al. (Dawson MA, senior author) · Nature 525(7570):538-542 2015
     used by Analysis (runnable): is there a shared cell-state signature behind non-genetic menin-inhibitor and BET-inhibitor resistance?, BRD2 - a bounded absence: zero KMT2A papers name it, it is inhibited by every BET compound used in this disease, and it is the paralogue most likely to carry the toxicity, BRD3 - named in the founding BET paper's own mechanism and in one title since, and not once separated from BRD4 by any experiment in this disease, CTNNB1 (beta-catenin) — the Wnt link inside DotCom, and the one piece of KMT2A biology that is not chromatin, Experiment: apply all three pressures and ask whether the survivors are the same cell, Fault trees, minimal cut sets and common-cause failure — reliability engineering on a buffered oncogenic program, Hypothesis: a single dormant leukemia stem cell state confers cross-resistance to menin inhibition, venetoclax and T-cell engagement at once — the common-cause failure that orthogonal combination therapy assumes away, Hypothesis: the ceiling on menin-interface disruption is cell-state plasticity, not target mutation, Which step is rate-limiting, and what compensates when you block it — the bite-back map for the causal chain
512. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25132265
     Endonuclease G initiates DNA rearrangements at the MLL breakpoint cluster upon replication stress.

     Gole B, Baumann C, Mian E, Ireno CI, Wiesmuller L · Oncogene 2015
     used by Apoptotic nucleases cut KMT2A, and cells that survive the attempt can carry a translocation, Replication stress and interstrand-crosslink repair as a cell state - an ATR dependency measured in mouse MLL-rearranged AML, and the same stress implicated in breaking the MLL locus in the first place, Replication stress, AID, base-excision repair and endonuclease G cut the KMT2A locus, RNF20 (BRE1A) — the H2B ubiquitin ligase that MLL-rearranged leukaemia needs, and that DepMap says every other cancer line needs just as much, Transcription–replication conflict as the candidate reason KMT2A-rearranged cells need the Fanconi pathway — a chain with two measured links and three inferred ones
513. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25822367
     Targeting the MLL complex in castration-resistant prostate cancer.

     Malik R, et al. · Nat Med 2015
     used by AR / androgen receptor - the best-supported partner in the absence set by independent-publication count, and the reason a menin inhibitor is in prostate cancer trials
514. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25730765
     The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

     Andersson AK, Ma J, Wang J, Chen X, Gedman AL, Dang J, et al. · Nature Genetics 2015
     used by Are the fusions temporary? No: the KMT2A fusion is the one thing that does not change between diagnosis and relapse, BMI1 - the self-renewal gene that KMT2A fusions can do without, because HOXA9 covers for it at the same locus, BMI1, CDKN2A and CDK6 are one circuit, not three genes - and in KMT2A-rearranged disease it has a loop nobody has measured, CDKN2A - one gene, two reviewed UniProt records with the same primary symbol, and a deletion that is three times rarer here than in the infant leukaemias next door, CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, CXXC4 (IDAX) - TET2's CXXC domain, sitting on a separate gene after an evolutionary inversion, and annotated cytoplasmic only by similarity, DNMT3A - an independent adverse factor in adult KMT2A-rearranged AML and conspicuously absent from paediatric disease, which is the whole finding, Enumeration of candidate cooperating lesions in KMT2A-rearranged leukaemia - what was written, what was recorded as a gap, and what was read and rejected, Experiment: does MLL-AF4 transform a staged fetal progenitor when it cannot transform cord blood?, FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants, Hypothesis: KMT2A::AFF1 is continuously required, not a hit-and-run initiator whose job is done once the epigenome is set, Hypothesis: the second hit in infant KMT2A-rearranged leukaemia is a fetal developmental window, not a mutation, If HOXA9 substitutes for BMI1 at CDKN2A, then a menin inhibitor should CREATE a BMI1 dependency that does not exist at baseline, IKZF1 - the defining co-lesion of every other high-risk B-ALL, and this disease does not use it until after treatment, Is the CpG address a contested resource? On current evidence, no - and the beat that went looking says so, Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal, KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells, KRAS as a co-mutation in KMT2A-r leukemia — the single most frequently co-mutated gene, and it still cannot start the disease, Measure the RAS allele fraction in CSF blasts and in paired marrow blasts from the same infant on the same day, NF1 - the only tumour-suppressor loss in this disease, and it is a deletion, so a mutation panel cannot see it, NF1 in KMT2A-r leukemia — one homozygous deletion, one missense, and the only loss-of-function co-lesion in the disease, No second driver means no second target - the quiet genome forecloses the combination logic that works in every other leukaemia, NRAS - the other RAS, the one whose 0.3% clone came back, and a UniProt record that lists HRAS1 as its own synonym, NRAS as a co-mutation in KMT2A-r leukemia — the one co-lesion that is specifically enriched in t(4;11), Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents, PAX5 - the most frequently hit non-KMT2A gene in infant KMT2A-rearranged ALL, and it is a deletion in one allele, not a mutation, PIK3R1 in KMT2A-rearranged infant ALL - the only cooperating lesion in this disease that was functionally proved to be activating, and it is an ITD, PTPN11 in KMT2A-r leukemia — named in every gene list, supported by almost no cases, PTPN11/SHP2 - non-recurrent in infant KMT2A-rearranged ALL, well drugged everywhere else, and the one leukaemia trial that carried a SHP2 inhibitor was withdrawn, RNA-targeting the fusion transcript: verdict THE LEAST HOPELESS of the three fusion-level routes, blocked by delivery rather than by biology, Subclonal cooperating lesions lost at relapse - what was actually measured, and why 'lost' is the wrong word, TET2 is NOT a CXXC protein - its CXXC domain is a separate gene, and it is DEPLETED in KMT2A-rearranged AML rather than enriched, TET3 - the CXXC reader whose domain prefers 5-carboxylcytosine, and the only CXXC-family gene ever found mutated in a KMT2A-rearranged cohort, The fusion junction itself as a small-molecule target: a candid verdict, The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good, The quiet genome, audited - the famous 1.3 mutations is a count of point mutations in the dominant clone, and all three of those words do work, The RAS-mutant subclone is where the leukaemia goes, not what it is - a dissemination modifier that a marrow aspirate systematically under-counts, TP53 - named in 84 entries of this graph, absent from the index genome study of the disease, and four different things depending on when you look, Treating a subclonal lesion is selection pressure applied to the clone you did not aim at, When one thing goes wrong, do several? In infant KMT2A-rearranged leukaemia the answer is no, and that cuts against the intuition
515. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25593305
     A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation.

     Zhang P, Chaturvedi CP, Tremblay V, et al. · Genes Dev 2015
     used by ASH2L SPRY and RBBP5 347-356: a phospho-reader contact gated by RbBP5 Ser350, and the only WRAD interface with a measured fold-change, WDR5 and RBBP5: the second arm of the WRAD hub, RBBP5 V375-D376-V377 into the same propeller face, co-crystallised with the MLL1 WIN peptide in one structure
516. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
     PDB 4X8N: Crystal structure of Ash2L SPRY domain in complex with phosphorylated RbBP5

     Zhang P, Chaturvedi CP, Tremblay V, et al. · RCSB Protein Data Bank 2015
     used by ASH2L SPRY and RBBP5 347-356: a phospho-reader contact gated by RbBP5 Ser350, and the only WRAD interface with a measured fold-change
517. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     Hein et al. 2015, supplementary Table S2 (mmc3.xlsx) sheet 'interactions', cell line MCP_ky_0003877, and workbook mmc4.xlsx sheet 'HeLa proteome'

     · Cell 163(3), supplementary material 2015
     used by Atlas-only interactome partners are predicted by how abundant the prey is, not by which bait was pulled - and if so this graph's interactome denominator is inflated, EBNA1BP2 (EBP2) - the DOT1L spoke with the HIGHEST stoichiometry and the WEAKEST evidence, and the case that shows why abundance is the third dimension, IBTK - the only one of the six DOT1L spokes with a reciprocal test, and its own pulldown in the same study does not find DOT1L, MAPK7 (ERK5) - a DOT1L partner on one 1:365 spoke of one atlas pulldown, and a kinase with real leukaemia literature that has never been connected to DOT1L, NIN (ninein) - a centrosomal scaffold recorded as a DOT1L partner under a UniProt isoform that UniProt itself calls dubious, PARP16 - graded A- in the DOT1L pulldown, the best of the six, and a tail-anchored ER membrane protein that cannot be in the nucleoplasm, Regress prey abundance against interactor confidence class across all 1,330 baits of the Hein atlas - the data are already downloaded and the run is an afternoon, The six unwritten DOT1L partners are not six findings - they are nine spokes of ONE GFP-DOT1L pulldown, and the source paper already graded them
518. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25921070
     Transcriptional elongation factor ENL phosphorylated by ATM recruits polycomb and switches off transcription for DSB repair.

     Ui A, et al. · Mol Cell 2015
     used by ATM - the DNA-damage kinase that phosphorylates three of the four KMT2A 3' partners, ATM phosphorylates ENL at conserved SQ sites and flips it from elongation to Polycomb repression - on sequence every KMT2A::MLLT1 fusion keeps, Induction chemotherapy phospho-inactivates KMT2A fusions through PIKK sites the partner retains - and a DNA-PK or ATM inhibitor would block that, PCGF1 — the PRC1.1 scaffold whose LOSS causes menin-inhibitor resistance, so it is a restraint on the leukaemia rather than a dependency of it, RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once
519. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26017030
     Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis.

     Herbaux C, Duployez N, Badens C, et al. · American Journal of Hematology 2015
     used by ATRX - DAXX's partner and the other arm of H3.3 deposition; in this disease its only signal is in the four lymphoid cell lines
520. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 25634209
     Interaction of BARD1 and HP1 Is Required for BRCA1 Retention at Sites of DNA Damage.

     Wu W, Nishikawa H, Fukuda T, et al. · Cancer Research 2015
     used by BARD1 (Q99728, 777 aa) - BRCA1's obligate partner, and the member of the cascade that actually touches the chromatin: its PxVxL motif at 569-573 binds HP1, and CTCF binds BARD1 rather than BRCA1 in an undamaged cell
521. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26287849
     Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations

     Hyman DM, Puzanov I, Subbiah V, et al. · New England Journal of Medicine 2015
     used by Basket and umbrella designs: pooling rare fusions into one trial
522. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26711339
     MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.

     Benito JM, Godfrey L, Kojima K, Hogdal L, Wunderlich M, Geng H, et al., Milne TA, Konopleva M · Cell Reports 2015
     used by BCL2 — the one co-dependency in this beat that already has an approved drug pointed at it, Import class 4: human myeloid cell lines standing in for infant B-lymphoid disease, Step 5 — The output program: HOXA9/HOXA10/MEIS1/PBX3 plus MEF2C, MYB, BCL2, FLT3 and PROM1/CD133, The imports that were never necessary: H3K79 methylation in KMT2A::AFF1 has its own literature, and this graph barely cites it
523. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26714909
     [Clinical analysis of 144 cases of infant leukaemia].

     Wen X, Guan X, Xian Y, Dou Y, Guo Y, Xiao J, et al. · Nan Fang Yi Ke Da Xue Xue Bao 2015
     used by Big liver, big spleen: the organomegaly numbers measured in infants, not pooled from children, Hypothesis: the spread in infant presenting-feature frequencies is mostly measurement, not biology, Rash: the one presenting feature that gets commoner the younger the baby is
524. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26166705
     BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks.

     Higgs MR, Reynolds JJ, Winczura A, Blackford AN, Borel V, Miller ES, Zlatanou A, Nieminuszczy J, Ryan EL, Davies NJ, Stankovic T, Boulton SJ, Niedzwiedz W, Stewart GS · Mol Cell 2015
     used by BOD1L (BOD1L1) — the top SETD1A co-dependency, and the only candidate in this cycle tested by CRISPR tiling in a KMT2A::AFF1 line
525. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26244121
     Congenital Acute Myeloid Leukemia with Unique Translocation t(11;19)(q23;p13.3)

     Yarbrough CK, Bandt SK, Hurth K, et al. · Cureus 2015
     used by Born with it: congenital KMT2A::MLLT1-type AML, a subdural haemorrhage that began before birth, and death on day four
526. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26496610
     A human interactome in three quantitative dimensions organized by stoichiometries and abundances

     Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, Gak IA, Weisswange I, Mansfeld J, Buchholz F, Hyman AA, Mann M · Cell 163(3):712-723 2015
     used by BRINP1 (DBC1/DBCCR1/FAM5A) - the last bait-supported partner of the six core proteins without an entry, a neural-specific BMP/retinoic-acid-inducible protein pulled down with DOT1L as bait in one quantitative AP-MS experiment and nowhere else, EBNA1BP2 (EBP2) - the DOT1L spoke with the HIGHEST stoichiometry and the WEAKEST evidence, and the case that shows why abundance is the third dimension, The six unwritten DOT1L partners are not six findings - they are nine spokes of ONE GFP-DOT1L pulldown, and the source paper already graded them, Two thirds of the curated interactome of this project's six core proteins is spoke-expanded - and the pairs this graph chose to write are significantly better than the ones it did not
527. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25407157
     Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the Children's Oncology Group

     Salzer WL, Jones TL, Devidas M, et al. · Pediatric Blood & Cancer 2015
     used by Bruising and petechiae: the bleeding signs of thrombocytopenia at presentation, COG AALL0631 — lestaurtinib in infant KMT2A-rearranged ALL: negative overall, positive where the drug actually hit, Dying in induction: the place where infant protocols actually differ, Fever and fatigue: two of the five headline signs cannot be elicited from a baby, Fever and infection: the reason most of these babies see a doctor, and the reason some of them die, Hepatosplenomegaly: the swollen abdomen that is often the first thing a parent notices, Leukaemia diagnosed in the first month of life: a different presentation and a different prognosis, Lymphoid-style versus myeloid-style consolidation — the question asked twice in 1,100 infants, and answered no both times, WBC 300, age 6 months, MRD 0.01%: three lines drawn by committees, not by biology
528. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26439302
     The PZP Domain of AF10 Senses Unmodified H3K27 to Regulate DOT1L-Mediated Methylation of H3K79.

     Chen S, et al. · Mol Cell 2015
     used by CALM-AF10 reaches DOT1L through exactly the same OM-LZ interface as KMT2A::MLLT10 - the recruitment transfers, the addressing does not, Is the drug target always in the retained half? An audit of the project's own framing, Losing the AF10 PZP reader is not a missing function - it is a removed brake, and putting it back cures the fusion, MLLT10 (AF10): the discarded PZP reader — the one partner where loss is proven to be the oncogenic event, MLLT10 / AF10 — domain architecture and residue coordinates, Re-supply the AF10 PZP module in cis to KMT2A::MLLT10 and ask whether transformation is suppressed
529. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26367869
     Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice.

     Wang H, Shun MC, Dickson AK, Engelman AN · PLoS One 2015
     used by Cardiomyocyte - the non-haematopoietic cell that two of this graph's drug targets are required in, which makes it the graph's clearest bystander-organ liability, HDGF - the third PWWP paralogue, which pulls down LEDGF but has the reader domain WITHOUT the domain that grips MLL, HDGFL2 / HRP-2 - the second IBD protein, which binds KMT2A at the same site with the same affinity and does NOT need menin to do it, PSIP1 makes two proteins and only one of them has the IBD: a p52 result is not a p75 result, and the knockout mouse removes both, The paralogue that covers for LEDGF: HRP-2 carries the only other IBD in the human proteome, substitutes for LEDGF in HIV integration, and the double knockout is embryonic lethal
530. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.journal-articlePMID 26516065
     Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

     Sotillo E, ..., Thomas-Tikhonenko A · Cancer Discovery 2015
     used by CD19 - the molecule this disease is treated by, named in 114 entries and written in none of them until now
531. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25538041
     Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.

     Aoki Y, ..., Ishikawa F · Blood 2015
     used by CD34 - named in 132 entries of this graph and written in none, and it does not mean what the graph has been using it to mean, CD38 - the one marker that is BRIGHTER in KMT2A-rearranged B-ALL, an antigen-targeted therapy that has already produced lineage switch, and an enzyme rather than a receptor
532. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 26308138
     Aggressive MLL gene rearranged CD7+ CD56+ myeloid / natural killer cell precursor acute leukaemia with extramedullary relapse in the uterus and breast.

     Soon G, ..., Wang S · Pathology 2015
     used by CD7 - the T/NK antigen on a B blast that flags KMT2A rearrangement and worse event-free survival, and the fourth antigen on the lineage-switch list
533. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25342715
     CDK6 as a key regulator of hematopoietic and leukemic stem cell activation

     Scheicher R, Hoelbl-Kovacic A, Bellutti F, Tigan AS, Prchal-Murphy M, Heller G, et al. · Blood 125:90-101 2015
     used by CDK4 - the other half of the class name, and it is NOT the gene this disease needs, CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true
534. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25664857
     Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription.

     Takeda S, Sasagawa S, Oyama T, Searleman AC, Westergard TD, Cheng EH, Hsieh JJ · J Clin Invest 2015
     used by CDKN2A - one gene, two reviewed UniProt records with the same primary symbol, and a deletion that is three times rarer here than in the infant leukaemias next door, TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes
535. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25395428
     Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia.

     · Blood 2015
     used by CDKN2A - one gene, two reviewed UniProt records with the same primary symbol, and a deletion that is three times rarer here than in the infant leukaemias next door, EZH2 - the Polycomb enzyme that collaborates with the fusion instead of opposing it, and that no single-agent inhibitor can switch off, Giving a translocation-promoting epigenetic drug in a translocation-defined B-lineage leukaemia, to infants, H3K27me3 - the repressive mark this graph argued about for seventy-seven cycles without ever writing an entry for it
536. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26265695
     Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation.

     Sperlazza J, Rahmani M, Beckta J, Aust M, Hawkins E, et al. · Blood 2015
     used by CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse
537. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25132270
     CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress.

     Sarmento LM, Póvoa V, Nascimento R, Real G, Antunes I, Martins LR, Moita C, Alves PM, Abecasis M, Moita LF, Parkhouse RM, Meijerink JP, Barata JT · Oncogene 2015
     used by CHEK1 (CHK1) - the node where this graph's chidamide synergy actually lands, and the reason that synergy is an HR-impairment argument
538. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26438359
     Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

     Mullenders J, Aranda-Orgilles B, Lhoumaud P, Keller M, Pae J, Wang K, Kayembe C, Rocha PP, Raviram R, Gong Y, Premsrirut PK, Tsirigos A, Bonneau R, Skok JA, Cimmino L, Hoehn D, Aifantis I · Journal of Experimental Medicine 2015
     used by Cohesin as an architectural co-lesion class — mutated in AML, associated with NPM1 rather than KMT2A, and leukemogenic on partial loss, CTCF/cohesin boundaries and the HOXA topological domain — the 3D scaffold the fusion program runs on, RAD21 - the cohesin subunit with the most break-prone sites in KMT2A-rearranged patients, and the degron experiment this graph keeps asking for
539. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 25805812
     Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia.

     Kühnl A, Valk PJ, et al. · Blood 2015
     used by CORRECTED: two of eleven CXXC readers HAVE been measured alongside a KMT2A fusion, and the result supports the menin-interface hypothesis, CXXC5 (RINF) - the one CXXC reader measurably down-regulated in KMT2A-rearranged AML, which is the only direction-of-change any family member has in this disease, Is the CpG address a contested resource? On current evidence, no - and the beat that went looking says so
540. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26321640
     CTCF Recruits Centromeric Protein CENP-E to the Pericentromeric/Centromeric Regions of Chromosomes through Unusual CTCF-Binding Sites.

     Xiao T, Wongtrakoongate P, Trainor C, Felsenfeld G · Cell Rep 2015
     used by CTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients
541. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26360610
     POL5551, a novel and potent CXCR4 antagonist, enhances sensitivity to chemotherapy in pediatric ALL

     Sison EA, Magoon D, Li L, et al. · Oncotarget 2015
     used by CXCR4 - named in eighteen entries of this graph with no entry of its own, and the one niche molecule with a drug, a paediatric trial and a direct KMT2A-r experiment, Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
542. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26188848
     The potential of clofarabine in MLL-rearranged infant acute lymphoblastic leukaemia.

     Stumpel DJ, Schneider P, Pieters R, Stam RW · Eur J Cancer 2015
     used by Cytarabine - the one conventional drug KMT2A-rearranged infant ALL is MORE sensitive to, and the only case in this beat where a mechanism changed a protocol
543. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26184334
     Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins.

     Bish R, Cuevas-Polo N, Cheng Z, Hambardzumyan D, Munschauer M, Landthaler M, Vogel C · Biomolecules 2015
     used by DDX6 - the only protein ever proposed to do for a cell what Tat does for the virus, on the strength of one 2016 paper
544. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 24798483
     Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement

     Bardini M, Woll PS, Corral L, Luc S, Wittmann L, Ma Z, et al., Jacobsen SE · Leukemia 2015
     used by Diagnosis versus relapse in the same child: relapse comes from a subclone that was already there and already quiescent, shown twice, seven years apart, by two unrelated methods
545. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25965993
     Dot1 histone methyltransferases share a distributive mechanism but have highly diverged catalytic properties.

     Stulemeijer IJ, De Vos D, van Harten K, et al. · Sci Rep 2015
     used by DOT1L methylates H3K79 non-processively - so the three states are one distribution, not three signals, H3K79me3 - the third methyl group, the one that needs the most enzyme flux and the one human DOT1L makes least of
546. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
     Hein et al. 2015, supplementary Table S1 (mmc2.xlsx) sheet 'bait cell lines' (1,330 rows) and Table S2 (mmc3.xlsx) rows for cell line MCP_ky_0004631

     · Cell 163(3), supplementary material 2015
     used by EBNA1BP2 (EBP2) - the DOT1L spoke with the HIGHEST stoichiometry and the WEAKEST evidence, and the case that shows why abundance is the third dimension, PARP16 - graded A- in the DOT1L pulldown, the best of the six, and a tail-anchored ER membrane protein that cannot be in the nucleoplasm
547. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26118502
     Inactivation of Eed impedes MLL-AF9-mediated leukemogenesis through Cdkn2a-dependent and Cdkn2a-independent mechanisms in a murine model.

     Danis E, Yamauchi T, Echanique K, Haladyna J, Kalkur R, Riedel S, et al. · Exp Hematol 2015
     used by EED - the PRC2 subunit this disease actually needs, with drugs in the clinic and zero leukaemia studies, H3K27me3 - the repressive mark this graph argued about for seventy-seven cycles without ever writing an entry for it, PRC2 - the complex, not the subunit, is the unit every experiment in this disease actually resolves
548. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26261306
     Dimerization of elongator protein 1 is essential for Elongator complex assembly.

     Xu H, Lin Z, et al. · Proc Natl Acad Sci U S A 2015
     used by ELP1 (IKBKAP/IKAP) - the Elongator scaffold that was first named for the IKK complex, is a paediatric-cancer predisposition gene, and has an RNA Pol II contact in IntAct
549. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 25847581
     ELP2 is a novel gene implicated in neurodevelopmental disabilities.

     Cohen JS, Srivastava S, et al. · Am J Med Genet A 2015
     used by ELP2 (STATIP1/StIP1) - the double beta-propeller of the Elongator core, whose informal name collides with a different human gene and whose STAT3 function is a by-similarity annotation
550. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26552700
     Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

     Picaud S, Fedorov O, Thanasopoulou A, Leonards K, Jones K, Meier J, Olzscha H, Monteiro O, Martin S, Philpott M, Tumber A, Filippakopoulos P, Yapp C, Wells C, Che KH, Bannister A, Robson S, Kumar U, Parr N, Lee K, Lugo D, Jeffrey P, Taylor S, Vecellio ML, Bountra C, Brennan PE, O'Mahony A, Velichko S, Muller S, Hay D, Daniels DL, Urh M, La Thangue NB, Kouzarides T, Prinjha R, Schwaller J, Knapp S · Cancer Research 75(23):5106-5119 2015
     used by EP300 — the acetyltransferase whose paralogue split is the finding: p300 is the 108th most KMT2A-selective gene, CBP is the 16,950th
551. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25943178
     A novel recurrent EP300-ZNF384 gene fusion in B-cell precursor acute lymphoblastic leukemia.

     Gocho Y, Kiyokawa N, Ichikawa H, Nakabayashi K, Osumi T, Ishibashi T, et al. · Leukemia 2015
     used by EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase, How common is ZNF384-rearranged leukaemia? Published answers span 1.6% to about 20% and the spread is almost entirely denominator, not biology, The necessary lesion in ZNF384-rearranged leukaemia is LOSS of the ZNF384 C-terminus, not GAIN of a fusion partner, The ZNF384 family is not the inverse of KMT2A::AFF1 - it is the SAME grammar written in the opposite gene order, and three of the four claims in the inverse framing are false
552. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26214589
     Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.

     Grunewald TGP, Bernard V, Gilardi-Hebenstreit P, Raynal V, Surdez D, Aynaud MM, Mirabeau O, Cidre-Aranaz F, Tirode F, Zaidi S, Perot G, Jonker AH, Lucchesi C, Le Deley MC, Oberlin O, Marec-Berard P, Veron AS, Reynaud S, Lapouble E, Boeva V, Rio Frio T, Alonso J, Bhatia S, Pierron G, Cancel-Tassin G, Cussenot O, Cox DG, Morton LM, Machiela MJ, Chanock SJ, Charnay P, Delattre O · Nat Genet 2015
     used by EWS::FLI1 builds its own enhancers at GGAA microsatellites, and a single inherited base change that lengthens one repeat raises the fusion's binding and the patient's risk. KMT2A fusions occupy pre-existing, invariant CpG islands - which is why this disease has no germline modifier of its target set, and why its mouse models work at all.
553. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25503383
     Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases

     Frock RL, Hu J, Meyers RM, Ho YJ, Kii E, Alt FW · Nature biotechnology 2015
     used by Experiment: bait the KMT2A breakpoint cluster region and sequence everything it joins to, in a fetal-like human progenitor, What maps a DNA break, and the fact that none of the modern instruments has ever been pointed at KMT2A in a blood progenitor
554. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25707806
     Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells.

     Walter D, Lier A, Geiselhart A, Thalheimer FB, Huntscha S, Sobotta MC, Moehrle B, Brocks D, Bayindir I, Kaschutnig P, Muedder K, Klein C, Jauch A, Schroeder T, Geiger H, Dick TP, Holland-Letz T, Schmezer P, Lane SW, Rieger MA, Essers MA, Williams DA, Trumpp A, Milsom MD · Nature 2015
     used by FANCL — FA core complex; rank 26 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all
555. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25999452
     Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies.

     van Dongen JJ, van der Velden VH, Brüggemann M, et al. · Blood 2015
     used by Flow-cytometric MRD: the fastest readout, and the one a lineage switch walks straight out of, MRD as a trial endpoint in KMT2A-rearranged leukaemia: high negativity rates, and almost none of them say which assay, MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest, Proximally biased V(D)J and IGHV6-1 in KMT2A::AFF1: the Ig MRD target is a moving target, and the clinic had already moved, What MRD-negative actually means: a quantitative range, a laboratory judgement, and three incompatible definitions
556. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26373280
     Frequent Derepression of the Mesenchymal Transcription Factor Gene FOXC1 in Acute Myeloid Leukemia

     Somerville TD, Wiseman DH, Spencer GJ, Huang X, Lynch JT, Leong HS, Williams EL, Cheesman E, et al. · Cancer Cell 28:329-342 2015
     used by FOXC1 - a mesenchymal forkhead factor derepressed in HOXA-high AML that blocks monocytic differentiation, with a real mechanism and zero published connection to KMT2A rearrangement
557. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25609649
     Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.

     Li X, et al. · Mol Syst Biol 2015
     used by FOXM1 - a one-panel MEN1 co-IP from a 4,119-row atlas, attached to a protein that is independently a validated MLL-rearranged leukaemia stem-cell dependency, PSIP1-FOXK2: a single TAP row from the same TF atlas as the RBPJ decline - kept as a lead rather than declined, because FOXK2 is a chromatin-recruiting forkhead expressed in lymphoid cells and LEDGF is a chromatin-recruiting tether, PSIP1-RBPJ - DECLINED. A 214-purification transcription-factor TAP atlas that this beat's own atlas heuristic failed to flag, and the Notch connection is the reason to say so out loud
558. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25822366
     DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.

     Chen CW; Koche RP; Sinha AU; Deshpande AJ; Zhu N; Eng R; et al. · Nat Med 2015
     used by H3K9ac - the mark KMT2A fusions pile up on their own targets, the one the AF9 reader actually binds, and the one a DOT1L inhibitor strips off first, H3K9me2 - named sixty times in this graph with no entry of its own, the mark that defines the lamina-associated domains the fusion's targets sit beside, and the only H3K9 methylation state ever measured at a KMT2A fusion's own binding sites, H3K9me3 - measured in KMT2A::AFF1 cells, in a supplementary figure, and it rises GENERALLY where H3K27ac falls SPECIFICALLY in the same experiment, H4K16ac - the one mark rule 80 actually rescued in this beat: elevated at MLL-AF9 targets in a supplementary figure, and the reason MLL1's own enzyme turns out to be dispensable, SIRT1 - not a fusion partner, the least required gene in KMT2A-rearranged lines, and the one target here where the direction of the drug is genuinely disputed
559. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.reviewPMID 25997831
     The oxygenase Jmjd6 - a case study in conflicting assignments.

     Böttger A, Islam MS, Chowdhury R, Schofield CJ, et al. · Biochem J 2015
     used by H3R2me2a - the asymmetric arginine mark two residues from H3K4 that LOCKS the WRAD module off the histone tail, and the first arginine mark node in this graph, H3R2me2s - the symmetric mark on the SAME residue as H3R2me2a, which permits rather than enhances WRAD access, and whose 'enhancing' half this graph inherited from the paper that was later revised, H4R3me2s - the repressive symmetric arginine mark that recruits DNMT3A, blocks a KMT2 enzyme's own PHD module, and is the ONLY arginine mark ever measured in a KMT2A-fusion system
560. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26447190
     Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies.

     Matthews GM, Mehdipour P, Cluse LA, Falkenberg KJ, Wang E, Roth M, et al. · Blood 126(21):2392-2403 2015
     used by HDAC1 - a class I eraser that has no dependency claim of its own in this disease, because removing it alone does nothing until HDAC2 goes too, HDAC2 - the buffering half of the class I pair, and the one class I enzyme a drug result in acute leukaemia has actually been pinned to, in AML rather than in a KMT2A fusion, HDAC3 - the only HDAC in this disease whose requirement was established genetically rather than by a drug, and the same experiment shows it is not fusion-specific, No HDAC-inhibitor result in this disease attributes to an HDAC enzyme - the only per-enzyme evidence is genetic, and it says the enzyme is not fusion-specific, Vorinostat (SAHA) - the only HDAC inhibitor given to newly diagnosed infants with ALL, in a 50-patient trial whose endpoint was tolerability and which reported four treatment-related deaths, all infectious
561. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-articlePMID 25688158
     Selective Inhibition of HDAC1 and HDAC2 as a Potential Therapeutic Option for B-ALL

     Stubbs MC, Kim W, Bariteau M, Davis T, Vempati S, Minehart J, Witkin M, Qi J, Krivtsov AV, Bradner JE, Kung AL, Armstrong SA · Clin Cancer Res 21(10):2348-58 2015
     used by HDAC6 - the one HDAC family member this graph refused, whose refusal named a falsifier that has been in the literature since 2020 and fires in the index fusion's own cell line
562. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26439010
     TAPBPR alters MHC class I peptide presentation by functioning as a peptide exchange catalyst.

     Hermann C, van Hateren A, Trautwein N, Neerincx A, Duriez PJ, Stevanović S, Trowsdale J, Deane JE, Elliott T, Boyle LH · Elife 2015
     used by HLA-B - the class I heavy chain the bivalency screen was actually read out on, and the locus that presents the one KMT2A epitope this graph has a structure for
563. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26403224
     HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia.

     Wu H, Eguchi-Ishimae M, Yagi C, et al. · British Journal of Haematology 2015
     used by HMGA2 (P52926) - a direct KMT2A::AFF1 target through the let-7b axis, and a recurrent fusion partner whose own fusions work by escaping a microRNA rather than by making a chimeric protein
564. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26437031
     Integrated molecular analysis of adult T cell leukemia/lymphoma

     Kataoka K, et al. · Nat Genet 2015
     used by HNRNPA2B1 — the panel's strongest KMT2A-selective RNA-layer gene after PTBP1, with ZERO records against MLL or KMT2A
565. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26436590
     The lincRNA HOTAIRM1, located in the HOXA genomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature

     Díaz-Beyá M, Brunet S, Nomdedéu J, Pratcorona M, Cordeiro A, Gallardo D, Escoda L, Tormo M, Heras I, Ribera JM, Duarte R, Queipo de Llano MP, Bargay J, Sampol A, Nomdedeu M, Risueño RM, Hoyos M, Sierra J, Monzo M, Navarro A, Esteve J · Oncotarget 6(31):31613-27 2015
     used by HOTAIRM1 lncRNA — the myeloid-differentiation transcript at the 3' end of HOXA, with a KMT2A-r evidence gap, miR-196b — the HOXA-cluster microRNA that is a direct KMT2A-fusion target and a genuine double agent
566. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25594862
     MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d etude des Tumeurs Endocrines

     Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Levy-Bohbot N, et al., Delemer B · J Clin Endocrinol Metab 100:1568-77 2015
     used by How long does menin have to be gone? Two months in a mouse islet, a decade or more in a human carrier, Pancreatic neuroendocrine tumours in MEN1: the manifestation that kills, and the one the animal data points at, Pituitary adenoma in MEN1: the third manifestation, and the one that matters most for a growing child, Primary hyperparathyroidism in MEN1: the first and commonest consequence of losing menin
567. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26245978
     Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif.

     Tesina P, Čermáková K, et al. · Nat Commun 2015
     used by Hypothesis: LEDGF licenses elongation at fusion target genes rather than anchoring the fusion, which predicts that a LEDGF agent is epistatic with BET and CDK9 inhibition and invisible in a fusion-ChIP assay, What LEDGF actually does for the fusion: it brings AF4, CDK9, BRD4, P-TEFb and Ser2P Pol II to the target gene, and H4K16ac with them
568. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.reviewPMID 25740345
     MLL leukemia and future treatment strategies

     Marschalek R · Archiv der Pharmazie 2015
     used by Hypothesis: the KMT2A genomic breakpoint carries prognostic information that the field has been sitting on for twenty years, KMT2A major breakpoint cluster region (BCR1): intron 7 - exon 13, ~8.3 kb, Rolf Marschalek & Claus Meyer (DCAL, Goethe-University Frankfurt) — the world's KMT2A breakpoint dataset, The reciprocal fusion (AFF1::KMT2A and friends): a second oncoprotein that opens chromatin for the first, Two classes of KMT2A rearrangement keep the SET domain, and the graph says otherwise
569. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26381409
     The RNA binding complexes NF45-NF90 and NF45-NF110 associate dynamically with the c-fos gene and function as transcriptional coactivators.

     Nakadai T, Fukuda A, Shimada M, et al. (5 authors; senior author Hisatake K) · J Biol Chem 2015
     used by ILF3 / NF90 - a nucleolar dsRNA-binding coactivator whose chromatin residency was mapped in the same leukaemia line that proximity-labelled KMT2A
570. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25538250
     Osteoblast menin regulates bone mass in vivo.

     Kanazawa I, Canaff L, Abi Rafeh J, Angrula A, Li J, Riddle RC, et al. · Journal of Biological Chemistry 2015
     used by In a live mouse, losing menin in bone cells means less bone - and menin overexpression means more
571. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
     GSE68720 - Gene expression profiles of infant acute lymphoblastic leukemia, COG trial P9407 (Affymetrix GPL570, n=97, per-sample KMT2A fusion partner)

     NCBI Gene Expression Omnibus · NCBI GEO 2015
     used by IRX2 transcript is NOT AFF1-confined: re-deriving GSE68720 finds 1 of 16 KMT2A::MLLT1 infants positive, and that case is IRX2-positive with IRX1 off
572. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25593309
     Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.

     Gong F, Chiu LY, Cox B, Aymard F, Clouaire T, Leung JW, Cammarata M, Perez M, Agarwal P, Brodbelt JS, Legube G, Miller KM · Genes Dev 2015
     used by KAT2A / GCN5 - the SAGA catalytic subunit that reaches this disease through its complex rather than through its own symbol, and whose only chemical tool degrades its paralogue too, KAT2B / PCAF - named in an existing entry's own id and never written, and the only acetyltransferase in this graph whose substrate is a fusion partner protein, KMT2A / MLL1 — the gene that breaks, SMARCA2 (BRM) - the paralogue nobody measured, and the reason a DepMap rank cannot predict what a BRG1/BRM inhibitor does
573. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paperPMID 26237645
     Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.

     Jiang Y, Qian X, Shen J, Wang Y, Li X, Liu R, Xia Y, Chen Q, Peng G, Lin SY, Lu Z · Nat Cell Biol 2015
     used by KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit
574. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25872778
     Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2.

     Ueda T, Nagamachi A, Takubo K, Yamasaki N, Matsui H, Kanai A, Nakata Y, Ikeda K, Konuma T, Oda H, Wolff L, Honda Z, Wu X, Helin K, Iwama A, Suda T, Inaba T, Honda H · Blood 2015
     used by KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit
575. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25320243
     The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia.

     Van der Meulen J, Sanghvi V, Mavrakis K, Durinck K, Fang F, Matthijssens F, et al., Wendel HG, Van Vlierberghe P · Blood 2015
     used by KDM6A / UTX — a commonly asserted KMT2A partner that belongs to a different complex and points the opposite way
576. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26080397
     Nuclear matrix-associated protein SMAR1 regulates alternative splicing via HDAC6-mediated deacetylation of Sam68.

     Nakka KK, Chaudhary N, Joshi S, Bhat J, Singh K, Chatterjee S, Malhotra R, De A, Santra MK, Dilworth FJ, Chattopadhyay S · Proc Natl Acad Sci U S A 2015
     used by KHDRBS1 (Sam68) — an RNA-binding protein that holds the MLL-AF4 message DOWN, a class no dropout screen can find
577. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25751424
     NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1

     Aguilar-Arnal L, Katada S, Orozco-Solis R, Sassone-Corsi P · Nature Structural & Molecular Biology 22(4):312-8 2015
     used by KMT2A K1130 acetylation - the clock-controlled, SIRT1-erased site that every KMT2A fusion retains, 17 residues from the CXXC and 208 from the breakpoint, KMT2A K1133 acetylation - the better-evidenced half of the pair, and the one that appears in the CBP/p300 acetylome itself, KMT2A K1235 acetylation - inside the SIRT1-interaction region, retained, and the one member of the Choudhary quartet the source paper named and then never assayed, KMT2A K636 acetylation - the forgotten member of the Choudhary quartet, retained, and outside the SIRT1-interaction region, KMT2A-CLOCK: one paper, six IntAct records, and the bait/prey grade splits it down the middle - CLOCK falls in the discard bin and SIRT1 does not, from the same experiments, No acetyl-dead and no acetyl-mimetic KMT2A was ever put in a methyltransferase assay - the link from K1130/K1133 to catalysis runs entirely through SIRT1, and that is a weaker claim than the abstract makes it sound, Of the 90 papers citing the discovery of KMT2A acetylation at K1130/K1133, the only three that mention MLL-rearranged disease or AFF1 are reviews, and none mentions menin - salvaged from an agent the session limit killed, Resolve acetyl-K1130/K1133 occupancy on the fusion versus wild-type KMT2A in the same cell - the one experiment that makes a shared-sequence site interpretable, The 2015 paper did not discover the KMT2A acetylation site - it inherited it from the 2009 Choudhary acetylome, which was run in a cell panel that includes MV4-11, a KMT2A::AFF1 line, The clock/SIRT1-regulated MLL1 acetylation site maps to KMT2A K1130 and K1133 in human numbering, just N-terminal to the CXXC and 208 residues before the breakpoint cluster - so it is retained in every KMT2A fusion, The K1130/K1133 numbering is HUMAN, stated in the paper's own words, and the immunising peptide proves it a second time without relying on that sentence
578. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26638075
     A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.

     Gupta GD, Coyaud E, Goncalves J, Mojarad BA, Liu Y, Wu Q, Gheiratmand L, Comartin D, et al. (20 authors), Pelletier L · Cell 2015
     used by KMT2A-DRC5 - DECLINED. A ciliary dynein-regulatory-complex protein, recovered by BioID in a centrosome-cilium map, and the only one of 135 uncovered partners never mentioned anywhere in this corpus
579. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 26171280
     AF4 and AF4N protein complexes: recruitment of P-TEFb kinase, their interactome and potential functions.

     Scholz B, Kowarz E, Rössler T, Ahmad K, Steinhilber D, Marschalek R · Am J Blood Res 2015
     used by KMT2A::AFF1 has no mapped interface to DOT1L: it lacks both structurally defined recruitment modules, and the one complex-level route claimed for it is contested by reconstitution, What this beat read and did not use: bounded absences, bounded rejections and one bounded unreadable
580. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 25485838
     Mutations in the deubiquitinase gene USP8 cause Cushing's disease.

     Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M · Nat Genet 2015
     used by KMT2A::USP8, t(11;15)(q23;q21) - three patients, and the second instance of a deubiquitinase partner
581. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25399948
     Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3)

     Dreyer ZE, Hilden JM, Jones TL, et al. · Pediatric Blood & Cancer 2015
     used by Lymphoid-style versus myeloid-style consolidation — the question asked twice in 1,100 infants, and answered no both times
582. established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paperPMID 26167883
     A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks.

     Huang H, Stromme CB, Saredi G, Hodl M, Strandsby A, Gonzalez-Aguilera C, Chen S, Groth A, Patel DJ · Nat Struct Mol Biol 2015
     used by MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7
583. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25575120
     MED26 regulates the transcription of snRNA genes through the recruitment of little elongation complex.

     Takahashi H, Takigawa I, Watanabe M, Anwar D, Shibata M, Tomomori-Sato C, Sato S, Ranjan A, Seidel CW, Tsukiyama T, Mizushima W, Hayashi M, Ohkawa Y, Conaway JW, Conaway RC, Hatakeyama S · Nat Commun 2015
     used by MED26 — a common-essential Mediator subunit with a solved 87-residue domain and no ChEMBL target entity at all
584. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25817203
     Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.

     Borkin D, He S, Miao H, et al. · Cancer Cell 2015
     used by Menin dependence of KMT2A::MLLT3: the fusion the co-IP was done on, the largest named partner in the pivotal trial, and still no published response rate
585. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26635203
     MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology Wilms tumours

     · Nature Communications 2015
     used by MLLT1 / ENL — the reader that beat its own paralogue, with a degrader already in hand, The same reader domain, mutated instead of fused, causes a childhood kidney tumour
586. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26079538
     AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis.

     Park J, Schlederer M, Schreiber M, Ice R, Merkel O, Bilban M, et al. · Oncotarget 2015
     used by MLLT11 / AF1q — a 90-residue protein with no chromatin domain and no oligomerisation module, KMT2A partner in t(1;11)(q21;q23)
587. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25510485
     Evidence-based RT-PCR methods for the detection of the 8 most common MLL aberrations in acute leukemias.

     Burmeister T, Meyer C, Gröger D, et al. · Leuk Res 2015
     used by MRD by fusion transcript: fast, standardised, partner-limited - and structurally blind to KMT2A*
588. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25664853
     Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program

     Park SM, et al. · J Clin Invest 2015
     used by MSI2 (Musashi-2) — sustains the MLL stem-cell programme in mouse, and the myeloid DepMap arm disagrees in sign, The RNA layer scored for KMT2A-selectivity across 79 genes, lineage-split — PTBP1 is the only menin-shaped hit, and the IGF2BP family shows no co-dependency
589. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 26916002
     Hsp90 in Cancer: Transcriptional Roles in the Nucleus

     Calderwood SK, Neckers L · Advances in Cancer Research 129:89-106 2015
     used by NELFB (COBRA1) — the NELF scaffold, and the single least KMT2A-selective gene of the sixty least selective in the genome
590. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26701913
     ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization.

     · Elife 2015
     used by NRAS - the other RAS, the one whose 0.3% clone came back, and a UniProt record that lists HRAS1 as its own synonym
591. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26323318
     NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability.

     Parplys AC, Zhao W, et al. · Nucleic Acids Research 2015
     used by NUCKS1 (Q9H1E3) - a RAD51AP1 paralogue that binds the same DNA with weaker affinity, and whose measured phenotype is mitomycin-C sensitivity rather than the D-loop binding this graph reached for
592. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
     PDB entries 1KO6 and 2Q5X (NUP98 C-terminal autoproteolytic domain) and 5CEH (Structure of histone lysine demethylase KDM5A in complex with selective inhibitor)

     RCSB Protein Data Bank · RCSB PDB 2015
     used by NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13)
593. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26220994
     The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains

     Alekseyenko AA, Walsh EM, Wang X, et al. · Genes & Development 2015
     used by NUTM1 (NUT) - a testis-restricted, fully disordered protein that writes no mark and instead switches ON a writer, and the 3' partner of the KMT2A-wild-type infant B-ALL with the opposite prognosis
594. moderate confidence 3 of 5: One strong study, or several smaller consistent ones.reviewPMID 26463423
     Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

     Sanjuan-Pla A, Bueno C, Prieto C, Acha P, Stam RW, Marschalek R, Menendez P · Blood 2015
     used by Pablo Menendez & Clara Bueno (Josep Carreras Leukemia Research Institute, Barcelona) — cellular origin, fetal models and infant-specific drug resistance
595. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26594843
     Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors.

     Esposito MT, Zhao L, Fung TK, Rane JK, Wilson A, Martin N, et al. · Nat Med 2015
     used by PARP1 - the target whose inhibitors this disease was specifically shown to resist, and which three later papers combine anyway, RAD51 - the one repair protein measured AT the KMT2A translocation hotspot, and ATM controls how much of it loads there
596. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25911551
     Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia

     Garcia-Cuellar MP, Steger J, Fuller E, Hetzner K, Slany RK · Haematologica 100:905-913 2015
     used by PBX proteins are not constitutively nuclear: a MEINOX partner keeps them there by blocking export - and nobody has ever looked at PBX3 in a KMT2A-rearranged cell, PBX3 - the TALE cofactor the field says is non-redundant, and the experiment that says HOXA9 is the redundant one, The druggable node in the homeodomain code is the MEIS1-PBX3 interface, not the HOX-PBX one - and it is the only one nobody has attacked, The PBX3-MEIS1 dimer, not HOXA9, is the unit that reproduces the MLL-fusion transcriptome - and it turns the HOXA cluster on from underneath
597. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25898166
     CALM regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature.

     Miller SE, et al. · Dev Cell 2015
     used by PICALM (CALM) - the clathrin-assembly adaptor that is the 5' partner of CALM::AF10, Where wild-type PICALM actually is: coated pits, the Golgi, coated vesicles - and a nuclear pool nobody has explained
598. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 25552701
     Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology.

     Ishikawa Y, et al. · Haematologica 2015
     used by PICALM (CALM) - the clathrin-assembly adaptor that is the 5' partner of CALM::AF10, The non-chromatin half: CALM-AF10 breaks the cell's iron intake and the cells are chelator-sensitive in vitro - but iron restriction did not extend survival in vivo (corrected 2026-09-21), Where wild-type PICALM actually is: coated pits, the Golgi, coated vesicles - and a nuclear pool nobody has explained
599. weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paperPMID 26164398
     KMT2A (MLL)-MLLT1 rearrangement in blastic plasmacytoid dendritic cell neoplasm

     Yang N, Huh J, Chung WS, Cho MS, Ryu KH, Chung HS · Cancer Genetics 2015
     used by Plasmacytoid dendritic cell — the interferon cell that KMT2A-rearranged leukaemia occasionally becomes, and is more often mistaken for
600. strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paperPMID 26711264
     Role of Polycomb RYBP in Maintaining the B-1-to-B-2 B-Cell Lineage Switch in Adult Hematopoiesis.

     Cales C, Pavon L, Starowicz K, Perez C, Bravo M, Ikawa T, et al., Vidal M · Mol Cell Biol 2015
     used by Pre-pro-B cell (murine Hardy Fraction A) - the stage before pro-B, with germline immunoglobulin genes, and the stage RYBP loss actually removes, RYBP - the subunit that makes a variant PRC1 complex catalytically active, named by two entries in this graph and never written