Compare59 fusions
Two fusions, side by side
The atlas lines every fusion up against the same ruler. This does the opposite: pick two and read them against each other — how much evidence each carries, how confident that evidence is, and which parts of the biology they share. The middle panel is the useful one, because a connection that belongs to only one of a pair is either what makes that fusion different or a gap in what we have written about the other.
What they share, and what they do not22 shared · 537 left only · 103 right only
Connections here are what the graph has written down, not what is true of the biology. A partner studied by more laboratories has more connections, so a short “only” column can mean the entry is thin rather than the biology is simple.
Shared · 22
- ARID4B / SAP180 (Q4LE39) - the Sin3A-complex subunit that shares SIN3A's HDAC1-binding region, is in the MLL-fusion interactome, and is the second of only two epigenetic vulnerabilities a CRISPR screen found in KMT2A-rearranged ALL
- EP300 — the acetyltransferase whose paralogue split is the finding: p300 is the 108th most KMT2A-selective gene, CBP is the 16,950th
- Experiment: CRISPR knockout of CLEC12A in KMT2A-rearranged models, with and without a cooperating RAS lesion
- GSE252378 fragment BEDs: a complete KMT2A N-terminal / C-terminal antibody set in 27 patient samples across six fusion partners, deposited and until now unopened by this corpus
- 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
- In-silico digest of 81 modelled KMT2A fusion junctions: the peptide that would prove the fusion protein exists
- KDM1A (LSD1) — acts at the loci the fusion binds, spares normal stem cells, and still has never been shown to touch the fusion protein
- KMT2A / MLL1 — the gene that breaks
- Mechanism class 1 — chromatin and elongation hijack (KMT2A-r, NUP98-r)
- MYB — rank 17 of 17,728 for KMT2A selectivity, and the only node in this beat where partial, transient suppression eradicated leukaemia without stopping normal blood production
- Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents
- Partner import: when a mechanism measured in one fusion is asserted about another
- PROPOSED: swap the partner, hold everything else - KMT2A::MLLT3 versus KMT2A::AFF1 in LIN28B-null human fetal liver CD34+ cells
- RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once
- RS4;11 retains 2.5x more H3K79me2 than MOLM13 under EPZ5676 at every one of ten baseline deciles - and 0.71x under compound 10, with the sign reversing in deciles 5-10: the between-line difference survives the baseline confound and fails the drug replication, so it cannot be attributed to the fusion partner
- 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
- The CRISPR-ChIP H3K79 partition is a mouse MLL-AF9 result: resolved from GEO after the full text proved unreachable
- The deposited RS4;11 H3K79me2 table in GSE149183 is two-thirds MOLM13: 38,580 of its 57,794 rows are byte-for-byte identical to the MOLM13 file, so the index fusion is measurable at only 19,214 TSS entries
- The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential
- The non-synchronisable state: five KMT2A-rearranged lines refuse mimosine, double thymidine and nocodazole, and the fusion protein does not fluctuate through the cycle
- The pivotal menin-inhibitor paper reports that the drug does NOT globally displace MLL1 or the fusion from chromatin - menin goes, the fusion largely stays
- 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
Only KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23) · 537
- "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
- 14-3-3 theta binds AF4 at Ser588 and rides into the MLL-AF4 complex - the phospho-gated contact the fusion really does carry
- 465 KMT2A-r B-ALL cases from 1 month to 89 years: partner predicts MRD clearance independently of age
- A caveat that weakened the index fusion, wrongly: the MLL-AF4 spreading deposition is 30 SEM samples plus six other lines, all human
- A genuine small-molecule disruptor of an oncogenic oligomer DOES exist - 7.44 against the RUNX1::RUNX1T1 NHR2 tetramer - which corrects this graph's record; and its eighteen-year potency curve says the class is a chemistry problem, which is what this graph concluded for the wrong reason
- A junction-specific monoclonal antibody against a paediatric leukaemia fusion oncoprotein exists: clone TEL 6F2, raised against a 12-mer spanning the ETV6::RUNX1 fusion site and used for genome-wide ChIP
- A pocketless fusion already had its protein-protein-interface drug taken to phase I/II - and TK216 turned out to be a microtubule destabiliser, not an EWS::FLI1 antagonist. This is the closest thing the field has to a controlled failure of the interface hypothesis.
- A six-month-old with a week of coughing: KMT2A::AFF1 pro-B ALL presenting with extreme hyperleukocytosis
- A surfaceome-first screen for KMT2A::AFF1: 2,404 surface proteins, 169 expressed in the fusion's own cell lines, 15 fusion-enriched, 3 clean in normal tissue - and the two sets do not intersect
- A tested negative: neither fusion product alters DNA double-strand break repair
- ACIN1::NUTM1 - the commonest NUTM1 fusion in infants, cryptic to cytogenetics, and the only one with a human cell line
- 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
- AFF1 / AF4 — domain architecture and residue coordinates
- AFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing
- AFF1 AF4_int motif to AF9/ENL AHD: the index fusion's only documented elongation interface, and it competes with DOT1L
- AFF1 as the subtraction control: the refutation is WITHDRAWN - the degron is lost, not retained
- AFF1 occupancy does not distinguish fusion-occupied promoters from wild-type KMT2A promoters in primary infant KMT2A::AFF1 - reproduced at promoter resolution, and the corpus should stop reading a partner ChIP as a fusion readout
- AFF1 reaches P-TEFb only through AFF4, and the index fusion's elongation phenotype is therefore a claim about AFF4 availability
- AFF1-AFF4 heterodimerisation through the C-terminal homology domain: the one SEC interface KMT2A::AFF1 certainly keeps, defined by a 2.2 A structure of the wrong subunit
- AFF1-AS1 - the antisense RNA 151 bp from the index fusion partner's TSS, which Ensembl does not recognise and this project's promoter table cannot see
- AFF1::KMT2A (AF4-MLL), the der(4) product: what it is made of, residue by residue
- AFF1's modern proximity neighbourhood is four RNA-binding proteins - NPM1, RBM15, SBDS, ZRANB2 - and it barely overlaps AFF4's
- AFF1's own promoter window is occupied in 20 of 27 samples - top 4% of the whole table - and the call cannot be attributed to AFF1
- AFF1's promoter window is 92.5% AFF1-AS1's - worse than IRX2's 89.2% - and the project's promoter table has no row for the neighbour at all
- AK_7_3, a KMT2A::AFF1-derived fusion circRNA that holds down mitochondrial respiration and ROS in t(4;11) B-ALL - the only mitochondrial mechanism in this beat measured in the index fusion
- AKAP95 reaches this disease by two separate routes - through WRAD/DPY30 and through the retained KMT2A fragment - and only the second one survives the fusion
- ALDH1L2 (Q3SY69) - the second-largest fall in the serine/one-carbon panel (-3.40), named nowhere in this graph, zero of 1,258 DepMap lines require it, and a tumour SUPPRESSOR where it has been studied
- ALL-PO (CVCL_1069) — an infant KMT2A::AFF1 line that is already in DepMap and has never been screened
- An anti-MLL-C antibody in a t(4;11) cell is looking at two proteins at once
- An H3K4me3-reading PHD finger fused to NUP98 makes a potent leukaemia oncoprotein; the H3K4me3-reading PHD finger of KMT2A is deleted from every KMT2A fusion and reinstating it abolishes transformation. Same module class, opposite sign - and the one NUP98 fusion that carries KMT2A's PHD cassette is the weakest member of its family.
- 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
- Are the fusions temporary? No: the KMT2A fusion is the one thing that does not change between diagnosis and relapse
- 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
- At gene-body scale the AFF1-exclusive recurrent class is 6 against an exact institution-stratified null of 0.86 - but the singleton class is 63 against 74, so recurrence carries the signal and exclusivity alone does not
- At the 692 RS4;11 bins where an MLL1 N-terminus and menin co-occupy, VTP-50469 takes menin to 0.20 and DOT1L to 0.20, drops H3K79me2 to 0.66, and leaves MLL1-N-reactive material at 0.83 - four factors, one drug, one chromatin, and a clean ordering
- ATF3 (P18847) - the one cascade member the DOT1L inhibitor hits HARDER than the menin inhibitor, and a transcriptional REPRESSOR being counted as a stress output
- ATF4 / CREB2 (P18848) - the hub this graph inferred from its targets and never wrote, and its own transcript does not move under either menin inhibitor
- ATF5 / ATFX (Q9Y2D1) - the most reproducible repression in the earlier dataset, and the three probe values the graph quotes are SEM, not RS4;11
- ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it
- Attribution audit 1 of 5 - who co-purifies with KMT2A::AFF1: the inventory does not survive, the individual partner blots mostly do
- Attribution audit 2 of 5 - post-translational modifications on KMT2A::AFF1: nothing survives at peptide level, and the one strong PTM result is explicitly about the wild-type protein
- Attribution audit 3 of 5 - where KMT2A::AFF1 sits in the nucleus: the endogenous image does not survive, the overexpression images do and say something different
- Attribution audit 4 of 5 - the half-life and turnover of KMT2A::AFF1: this class SURVIVES, and it is the only endogenous fusion-attributable protein measurement this beat found
- 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
- AUGMENT-101 (NCT04065399) — the registration trial, and what 22.8% actually means
- AUGMENT-101: the partner composition of the trial that approved a menin inhibitor, with KMT2A::AFF1 at n=2 evaluable
- BAHCC1 - a BAH-domain H3K27me3 reader that an MLL fusion binds and upregulates in mouse, and the locus carrying the two largest MLL1-N-reactive rises under a menin inhibitor in human RS4;11
- BCL2 — the one co-dependency in this beat that already has an approved drug pointed at it
- 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
- BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11)
- BET bromodomain inhibition in KMT2A-rearranged leukemia — spectacular preclinically, stalled clinically
- Bite-back: a target nominated from an imported mechanism inherits a fusion the index disease does not have
- BLIN-3 (CVCL_QW47) — a three-month-old's KMT2A::AFF1 line used to show the pro-B to pre-B block can be pushed
- Blinatumomab in infant KMT2A-rearranged ALL — the largest single outcome gain in thirty years
- BOD1L (BOD1L1) — the top SETD1A co-dependency, and the only candidate in this cycle tested by CRISPR tiling in a KMT2A::AFF1 line
- Bortezomib is called an NF-kB inhibitor, and in MLL leukaemia it does two different things in two lineages — neither of which is reliably NF-kB in the lymphoid one
- Bounded absence: every chromatin measurement under a menin inhibitor is in an adult-derived line, and none is in an infant KMT2A::AFF1 model
- Bounded absence: no published study has tested whether a KMT2A fusion GAINS chromatin sites under a menin inhibitor - and the same pipelines found gains for two other proteins when they looked
- Bounded failure: the one unresolved source that is actually about the index fusion
- Bounded unreadable: the only affinity purification of a SET-retaining KMT2A-derived fusion complex fails all four routes, and the molecule is the reciprocal product
- 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
- BRD9::NUTM1, t(5;15)(p15.33;q14) - one fusion is enough to make infant B-ALL in a mouse, and it is the one that behaves best in a child
- 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
- BUD13 - a RES-complex splicing factor 1.66 Mb from KMT2A on 11q23.3, whose one chromatin paper puts it in the soluble fraction
- Catalytic-dead versus degrader: a four-arm test that resolves the HDAC7 direction conflict and supplies the pharmacodynamic marker this drug class has never had
- CBFA2T3::GLIS2 supplies its own CAR-T antigen - FOLR1 came out of a list of fusion-specific genes in an isogenic human model. KMT2A-rearranged leukaemia is treated with a LINEAGE antigen it can abandon, or with one a drug has to create; nobody has built the fusion-specific surface list for KMT2A::AFF1.
- CBFA2T3::GLIS2, inv(16)(p13.3q24.3)
- CBFB — domain architecture and residue coordinates
- CBX8 — the one place in this interactome where two good papers flatly disagree, and DepMap takes a side
- CCND3 (cyclin D3) — the scan's rank-4 hit, and the only one of the four with a drug class already in children
- 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
- CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true
- Cell type or the fusion? MV4-11 LOOSENS the confound the graph's own lineage split was built on - but its founding paper calls it biphenotypic
- Cell-surface capture proteomics on an isogenic human KMT2A::AFF1 model against its matched normal progenitor - the experiment an mRNA screen cannot replace
- CHAC1 / BOTCH (Q9BUX1) - the largest single effect in the whole menin-inhibitor response (-5.11 log2) and a glutathione-degrading pro-apoptotic enzyme, named nowhere in this graph until now
- CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse
- 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.
- Chromatin-bound XPO1 as a shared, druggable address for HOXA-driven leukaemia - and the objection that it may be a general chromatin cofactor rather than an address at all
- Combine an IKK inhibitor with a clinical menin inhibitor in a KMT2A::AFF1 B-ALL line, and read out fusion OCCUPANCY rather than viability
- Competing model 3: reciprocal status is a proxy for where the break fell, and the thing that changed is the DIRECT product
- Cord blood does transform — when the translocation is engineered rather than expressed
- Correcting the fusion with genome editing: verdict NOT FEASIBLE for infant leukaemia, though intron-targeted disruption is a real published strategy
- CORRECTS A DISPATCH PREMISE: GSE149183's menin-versus-DOT1L-inhibitor head-to-head exists in MOLM13 (KMT2A::MLLT3) ONLY. RS4;11 - the index fusion - is in the series but carries H3K79me2 alone, with no VTP-50469 arm, no MEN1 ChIP and no DOT1L ChIP, and the two arms are on different genome builds
- CREBBP (CBP) — binds the KMT2A transactivation domain, which no fusion keeps
- CRISPR-engineered t(4;11) in human fetal liver — the only model that reproduces infant-specific biology
- CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology
- CSNK2B / CK2beta (P67870) - the regulatory subunit of casein kinase 2, in the pan-MLL-fusion core, with no CSNK2B-and-KMT2A literature at all
- CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it
- 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
- 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
- Cyclophosphamide - where the KMT2A literature reports two different activated oxazaphosphorines and only one of them is this drug's metabolite
- Dataset: cBioPortal - open, easy, and containing exactly two KMT2A::AFF1 fusion records
- 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
- 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
- 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
- Differentiation syndrome is the one human pharmacodynamic readout KMT2A-rearranged leukaemia already shares with APL - and in APL it is a complication of a cure, while here it is a complication of a 30% response rate
- Does KMT2A::AFF1 bind the histone chaperone SET/TAF-I beta, and does that contact overlap the menin-binding motifs? A co-IP and a peptide competition
- Does KMT2A::AFF1 change histone turnover at its target genes, or does it read a chromatin state it did not make?
- Does menin inhibition have any MHC class II headroom to work with in B-precursor infant ALL? A flow cytometry experiment on samples that already exist
- 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
- Does WDR5 move between complexes? An acute KANSL1 degron with WDR5 co-IP, WDR5 CUT&RUN and H4K5/K8/K16ac readout in a KMT2A-rearranged line
- DOT1L — the target where excellent chemistry met an indirect interaction
- 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
- Download and bin GSE127507's nine RS4;11 tracks (1.99 GB), rebuild a human binner, and score the eviction gradient in the index fusion KMT2A::AFF1 - the one measurement that would move this finding from KMT2A::MLLT3 to the disease this graph is about
- DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose
- DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus
- EAF1 — the interactor with an actual subnuclear phenotype: an MLL fusion evicts it from Cajal bodies, and the bodies themselves fall apart
- EAF2 (U19) — the EAF paralogue whose ELL-binding domain is a mapped tumour-suppressor module, described entirely in prostate cancer
- EIF2AK4 / GCN2 (Q9P2K8) - the amino-acid-sensing eIF2alpha kinase: transcript flat, and NOTHING has ever been published about it in any KMT2A-rearranged system under either name
- 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
- ELOVL1 - the fatty-acid elongase that infant MLL-AF4 ALL retains from its fetal origin, and the lipid enzyme on the opposite side of the divide from ACSL4
- EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase
- EPHA7 - ephrin type-A receptor 7, a published direct promoter target of the ALL1/AF4 (KMT2A::AFF1) fusion protein
- 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
- ETO2::GLIS2 rewires chromatin in stages and hijacks the osteogenic homeobox factor DLX3 as its first required step — a genome-edited human iPSC model that resolves leukaemia initiation into an ordered sequence
- ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22)
- Every MS-evidenced KMT2A modification site, flagged retained or lost against the breakpoint - and the retained portion is NOT enriched for acetylation once you use the right null
- 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
- Every published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions
- Every WRAD subunit, DOT1L, ENL, AF9 and LEDGF carries a cited histone-mark finding and none carries an epigenetics field - 12 of the 32 index-fusion core proteins are pure notation gaps, 9 are covered, and the 11 with nothing are all on the negative-regulatory side of elongation
- 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.
- EWSR1::FLI1 (EWS-FLI1), t(11;22)(q24;q12)
- Experiment: build the missing KMT2A::AFF1 degron and titrate it — what fractional occupancy does the program actually need?
- Experiment: combinatorial dose-titration of the HOXA9/MEIS1 program to find its minimal cut set
- Experiment: does MLL-AF4 transform a staged fetal progenitor when it cannot transform cord blood?
- Experiment: five-fraction subcellular blot of a t(4;11) line, with a menin-inhibitor arm - converting thirty years of unattributable images into attributable numbers using only existing antibodies
- Experiment: long-hold degron depletion of endogenous KMT2A::AFF1, to ask whether the leukaemic program recovers without the fusion
- Experiment: measure KMT2A-AFF1 spatial proximity in the human fetal progenitor, in the cell and at the time the translocation actually happens
- Experiment: put four residues back - the minimal add-back control the PHD3 result has never had
- Experiment: spike-in-calibrated, fusion-attributable occupancy of KMT2A::AFF1 in the first 24 hours of menin inhibition, scored for gains as well as losses
- Experiment: titrate wild-type KMT2A up and down in one leukemia cell and watch what happens to the fusion's grip on chromatin
- FACT (SPT16-SSRP1) - the chromatin arm of transcription elongation, and a clean negative result for the KMT2A::AFF1 interactome
- Fetal CD19+CD34+CD10-negative PreProB progenitor — a cell that exists before birth and almost not at all after
- Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL
- 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
- First systematic enumeration of the KMT2A fusion interactome, and the diff against this graph
- FLT3 / CD135 — the strongest non-tether co-dependency, and a target the field may have written off on a badly executed trial
- FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants
- FLT3 in ZNF384-rearranged leukaemia - the fusion builds its own enhancer 25 kb upstream, and gilteritinib works in xenografts
- FLT3-ITD signals from inside the cell, not from the surface - and whether it is the ER or the Golgi decides which pathway fires
- Forty-five percent of t(4;11) patients express a KMT2A fusion transcript that keeps the whole WRAD interface
- Four hours of MS67 in MV4;11, two KMT2A antibodies: the cheapest test of whether WRAD reaches the fusion or only wild-type KMT2A
- 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
- 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
- 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
- FUT4 - the myeloid alpha-1,3-fucosyltransferase, a hub gene of the KMT2A-rearranged expression module, and the gene HGNC once officially called CD15
- 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
- GSE159608 — 419 automated CUT&Tag libraries across 7 KMT2A-rearranged primary patient samples, 5 lines and a normal CD34+ donor, including KMT2A fusion occupancy, a menin-inhibitor arm in SEM, and three single-cell CUT&Tag libraries
- GSE252378 holds eight KMT2A::AFF1 oncoprotein panels from two centres, not the three this corpus had used
- GSE252378 holds the only AFF1 CUT&RUN in primary KMT2A::AFF1 patient material - four libraries across two patients, three disease states and the SEM cell line, all hg38
- GSE299100 supplies the vehicle-versus-vehicle pair that neither GSE260742 nor GSE127507 could - two independent control hairpins, both DMSO, same date, uniformly processed to hg38_rmdup.tdf, for MEN1, MLL1 and input - in MV4-11, which Cellosaurus confirms carries KMT2A::AFF1 though it presents as monocytic rather than the infant B-ALL this project studies. It also holds MEN1 and MLL1 ChIP under five different menin inhibitors in that line, and the six control files total 1.87 GB
- GSM8006584 names its antibody KMT2A-C1 in its title, its characteristics field and its own filename, and KMT2A-C2 in its description - so keying the antibody off the free-text description gives patient TB-92-0488 two C2 libraries and no C1
- H2BK120ub (H2Bub1) — the ubiquitin tag on histone H2B that licenses H3K79 methylation, and the mark this graph was missing
- 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
- H3K4me2 - the LSD1 substrate, and the only histone mark ever compared head-to-head between two KMT2A fusion partners in human cells
- Haemogenic endothelium — the vessel-wall cell that gives birth to blood
- 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
- Half this graph's claims are unopposed; these are the ones that matter
- HCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind
- 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
- 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
- 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
- HNRNPA2B1 — the panel's strongest KMT2A-selective RNA-layer gene after PTBP1, with ZERO records against MLL or KMT2A
- HOXA7 - the one HOXA paralogue besides HOXA9 with a published loss-of-function requirement for MLL-fusion transformation, and the requirement was shown in vitro only
- HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it
- HOXB4, the one direct IRX1 target with ChIP evidence, carries no oncoprotein in any of seven infant patients
- Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion
- Hypothesis: KMT2A::AFF1 is continuously required, not a hit-and-run initiator whose job is done once the epigenome is set
- 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
- Hypothesis: the reciprocal AFF1::KMT2A product protects only when it is structurally complete, so its prognostic effect is a breakpoint class in disguise
- Hypothesis: transfer-RNA and ribosome biology is a genuinely empty cell in KMT2A-rearranged leukemia, and translational capacity may be the unmeasured dependency
- Hypothesis: what the KMT2A half loses is control of its own abundance, not control of its activity
- I-BFM childhood KMT2A-r AML (n=1,130): the 3-prime partner defines two risk groups that differ by 24 EFS points
- I3IN-002 — the first small-molecule IGF2BP3 inhibitor with in vivo activity in an MLL-Af4 model
- iALL-HOXA9 — the HOXA-high state of infant KMT2A::AFF1 ALL, and the one everything is modelled on
- iALL-IRX1 — the HOXA-negative, IRX1-high state of infant KMT2A::AFF1 ALL
- 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
- ICOSLG on infant t(4;11) blasts converts T cells into regulatory T cells - the one immune-evasion route measured in this exact disease, in this exact age group
- 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
- IKZF3 / Aiolos (Q9UKT9) - the B-lymphoid transcription factor that goes UP under both inhibitors, regulates BCL2, and is a degradable drug target
- IMSUTi002-A-2 (CVCL_C9HE) — a doxycycline-inducible KMT2A::AFF1 iPSC line, and the isogenic design nobody in this graph has used
- In an unsupervised 5 kb correlation of 41 SEM libraries, both KMT2A N-terminal AutoCUT&RUN libraries have menin as their single nearest neighbour - the menin-interface hypothesis appearing as the top-level structure of an analysis that was not looking for it
- In human KMT2A::AFF1 MV4;11 (monocytic, not B-lineage), the vehicle-versus-vehicle noise floor is 9.4% at the top 0.1% of menin/MLL1 sites and 0.1-2.6% in every other stratum - so cycle 102's borrowed 4-10% band is about right AT THE PEAKS and four to five times too generous everywhere else, and it was applied everywhere
- In human RS4;11 (KMT2A::AFF1), menin occupancy at its own top 0.1% of 2 kb bins falls 14.9x to 2.0x over the track median and its share of total coverage falls to 0.200 - reproducing Q117's murine FLAG-MLLAF9 figures (15.9x to 3.0x, ratio 0.179) to within 1.3-fold on all five statistics
- 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
- 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
- In leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that.
- In SEM, the infant-derived KMT2A::AFF1 line, VTP-50469 lowers H3K4me3 at menin-bound sites by 23% relative to H3K4me3-matched menin-free sites (95% CI 13-33%), while the DOT1L inhibitor EPZ-5676 changes it by 1% (CI -4 to +6%)
- In St. Jude paediatric AML, 2 of the 6 ARID1A-mutant cases are KMT2A-rearranged and BOTH ARID1A mutations are TRUNCATING frameshifts in KMT2A::MLLT10 cases - so the exact combination cycle 86 showed the ARID1B dependency is confined to DOES occur in patients, and cycle 88's empty DepMap intersection is a cell-line sampling artefact rather than a fact about the disease. The paediatric ALL cohort returned zero ARID1A mutations, which is panel coverage and not biology
- In the deposit paper's own target-gene table, the AFF1-exclusive class is 64 genes against a permutation null of 2.3, and it survives call-rate matching, institution stratification, B-lineage restriction and patient collapse
- In the human index fusion the menin inhibitor subtracts MENIN and leaves MLL1-N-reactive material in place at the same sites - so the drug's chromatin action is decoupling rather than eviction, and what this literature calls fusion eviction is a menin measurement
- In-utero origin, proven: clonotypic KMT2A::AFF1 junctions found in the patient's own newborn blood spot
- Infant acute lymphoblastic leukaemia (ALL diagnosed under 1 year of age)
- Infant BCP-ALL (n=175): KMT2A::AFF1 2-year EFS 36% versus 37% for every other partner (P=0.9)
- IntAct curates SEVEN MLL fusion proteins as first-class interactors - ENL, AFF4, AF9, GAS7, ELL, AF6 and CALM - and not the index one
- 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 carries the KMT2A::AFF1 oncoprotein in exactly the patients where HOXA does not — seven patients, GSE252378
- 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
- IRX2 - the IRX-cluster neighbour that is this disease's own prognostic gene, activated only in KMT2A::AFF1, and never written here until now
- IRX2 is not fusion-occupied at promoter scale in GSE252378: 0 of 27 samples, against a null of 2.73
- 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 KMT2A::AFF1 leukemia epithelial or endothelial? No — it is haematopoietic. But the question is a good one
- 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
- ITGA4 (VLA-4) and NG2 — the niche-adhesion axis of KMT2A-rearranged B-ALL, and the one approved drug that hits it
- JADE3 / PHF16 (Q92613) - the HBO1-complex scaffold with the strongest pan-fusion evidence in this beat, and an independent published contact with MLL
- JDI-12 - published as a JMJD1C inhibitor that preferentially kills KMT2A-rearranged leukaemia and spares cord blood, then used as 'KDM3i' to CREATE KMT2A rearrangements in cord-blood progenitors, by two papers that do not cite each other
- 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
- Junction RT-PCR is the one routine assay in this disease that IS fusion-specific - and it is structurally blind to KMT2A*
- KAT7 / HBO1 — an enzyme, a leukaemia-stem-cell dependency, and an inhibitor already in a crystal
- KAT8 (MOF) — a genuine KMT2A partner that binds the half of KMT2A the fusion discards
- KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR
- KDM6A / UTX — a commonly asserted KMT2A partner that belongs to a different complex and points the opposite way
- 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
- KHDRBS1 (Sam68) — an RNA-binding protein that holds the MLL-AF4 message DOWN, a class no dropout screen can find
- Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal
- KMT2A 747-755 on HLA-B*07:02: a phosphoneoantigen from the half of KMT2A every fusion keeps, with seven crystal structures and a cognate TCR
- KMT2A minor breakpoint cluster region (BCR2): intron 20 - exon 24
- KMT2A rearrangement creates a requirement for the FA ubiquitin-transfer module — the claim, its prior, and the four results that would kill it
- KMT2A sits in the 14-3-3 proximity neighbourhood, and the YWHAG link reproduces across two independent studies
- KMT2A-rearranged acute leukemia across all ages: infants are 4% of it
- KMT2A::AFDN (MLL-AF6), t(6;11)(q27;q23)
- 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
- 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 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
- KMT2A::AFF1 has no measured fusion-specific interactome: the one dataset that appears to supply one is a rank-selected tail in the wrong lineage, and the question is open rather than answered badly
- KMT2A::AFF1 oligomerises through the retained AFF1 CHD, putting the commonest fusion in the oligomerisation class
- KMT2A::AFF1 retains THD2 by position, so the HBO1 contact can apply to it — but the paper that established that contact tested MLL-ELL, MLL-AF6 and MLL-AF10, never the index fusion
- KMT2A::ELL (MLL-ELL), t(11;19)(q23;p13.1)
- KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour
- 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
- KMT2A::SEPTIN11 (MLL-SEPT11) — the fusion that cytogenetically impersonates t(4;11)
- KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers
- Knock a tag-plus-degron cassette into the endogenous KMT2A::AFF1 allele in SEM - one construct that makes five claim classes attributable
- 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
- 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
- LAMP5 (BAD-LAMP) - a direct MLL-fusion target gene, a proposed immunotherapy antigen, and a brain protein
- LDB1::KMT2A - the clearest statement in this literature that a sarcoma fusion keeps KMT2A exons 4 to 36 and discards exons 1 to 3
- 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
- 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
- LEF1 — the Wnt/β-catenin DNA-binding factor of the T-lineage, named as an MLL-AF4-specific interactor in a T-ALL cell line and with essentially no B-lineage or KMT2A literature
- 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 - a one-row BioID prey of KMT2A that a 2026 Blood paper shows is REQUIRED for KMT2A::AFF1 to transform human fetal cells
- 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
- LMO2 (rhombotin-2) - a bridging LIM-only protein, higher in pro-B and MLL-rearranged B-ALL, anti-selective in KMT2A-rearranged lines, and a physical partner of the KDM5A module that NUP98::KDM5A retains
- Lost from the KMT2A half: the four-residue HCF-binding motif (DHNY, aa 1799-1802)
- Lost from the KMT2A half: the WIN motif and the whole WRAD interface (aa 3762-3767, Arg3765)
- LPP (lipoma-preferred partner) - a KMT2A fusion partner in acute monoblastic leukaemia whose day job is adhesion mechanotransduction, and which is barely expressed in leukocytes
- 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
- Lymphoid-primed multipotent progenitor (LMPP) — the bi-potent cell that explains how one fusion makes two lineages
- 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
- 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
- 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
- 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
- MBM2, the second menin-binding motif of KMT2A (residues 23-40): 26-fold weaker than MBM1, never separately co-crystallised, and the only part of the menin grip a drug is not aimed at
- 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
- MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7
- 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
- Measure the pausing index at KMT2A::AFF1 target genes — the one number the whole pausing argument turns on, and it has never been reported
- MED19 - the Mediator subunit curated against an engineered MLL-AFF4 fusion protein, and the one REST uses to deliver G9a
- 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
- MEN1 / menin — the adaptor the fusion cannot work without
- miR-9 — the most MLL-specific microRNA in AML, encoded at three separate loci nobody has disambiguated
- Mixed phenotype acute leukaemia (MPAL) and acute leukaemia of ambiguous lineage
- MLL fused to MURINE Af4 in human CD34+ cells — the model that works, and the swap that makes it work
- 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
- MLL was reported at regions attached to the nuclear envelope in 2000, which is indirect evidence at the lamina that this graph currently records as absent
- Mll-AF4 mouse genetics — B-lineage tumours, long latency, and never infant pro-B ALL
- MLLT1 / ENL — the reader that beat its own paralogue, with a degrader already in hand
- MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is
- MLLT6 (AF17) — the fourth KMT2A fusion partner inside DotCom, and the only one no cell needs
- Monoblast — the immature monocyte that names FAB M5a, the dominant morphology of congenital KMT2A leukaemia
- MRD by fusion transcript: fast, standardised, partner-limited - and structurally blind to KMT2A*
- MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction
- MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest
- MV4-11 (CVCL_0064) — KMT2A::AFF1, yes, but a ten-year-old's acute monocytic leukaemia with FLT3-ITD
- 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
- NG2/CSPG4 is the one antigen in the whole surfaceome that KMT2A::AFF1 itself drives - and it is a pericyte and vascular protein, at 124.5 nTPM in normal blood vessel and 246 TPM in tibial artery
- Niche biology HAS been measured in KMT2A-rearranged disease - but in the index fusion itself there is essentially one marrow-niche molecular experiment, from 2011
- No experiment has ever ASKED whether MTA2, MBD3, GATAD2A or SIN3A binds a KMT2A fusion - four of them were nonetheless in the lysate of a seven-fusion pulldown, and the class of that absence is measured-not-reported, not never-measured
- No fusion oncoprotein in any family has a published replication-protein-A measurement: 23 queries across five fusion families and four spelling variants each, every querytranslation read back, zero records - so the PI's analogy dimension for RPA has no comparator at all, and the index fusion's single locus-level result is the entire field
- No KMT2A fusion junction peptide has ever been reported - the one measurement that would prove the protein exists has not been published
- 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
- 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
- NPM1::ALK (NPM-ALK), t(2;5)(p23;q35)
- NRAS as a co-mutation in KMT2A-r leukemia — the one co-lesion that is specifically enriched in t(4;11)
- 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
- NUP98 fusions share the menin dependency (confirmed preclinically) — and the partner-supplied reader/writer module is not why
- NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13)
- NUP98::KMT2A, inv(11)(p15q23) — the NUP98 fusion that contains KMT2A and is menin-inhibitor RESISTANT
- Of every antigen this project names, only NG2, LAMP5 and CD123 are present on all three KMT2A::AFF1 cell lines - CD19 is at 0.2 nTPM in MV4-11 and CD33 at 2.3 in RS4;11
- On an absolute scale, H3K79me2 in the index fusion falls 52-fold (EPZ5676) to 91-fold (compound 10) by day 9 and NOT ONE of 17,341 measurable genes holds its signal - the first absolute-scale chromatin statement this project has been able to make about KMT2A::AFF1
- 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
- One blot: phospho-eIF2alpha and ATF4 protein in RS4;11 under VTP-50469, with a dose-response and a DOT1L comparator arm
- One demethylase family sits at both ends of this disease - KDM3B gates whether KMT2A rearranges, JMJD1C is what the resulting fusion needs to survive - and a single compound hits both, so its therapeutic index runs in opposite directions in the two cell populations it reaches
- One experiment that decides whether KDM4C is a target or the KDM4 family is: paralogue rescue of SD70 sensitivity in SEM
- One immunoprecipitation that decides whether 14-3-3 touches KMT2A at all
- 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
- Open ground: the questions in this graph that nobody in the landscape appears to be working on
- p279 and p318: one infant, two diseases, and an oncoprotein target map that does not carry over
- 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
- Pablo Menendez & Clara Bueno (Josep Carreras Leukemia Research Institute, Barcelona) — cellular origin, fetal models and infant-specific drug resistance
- PAF1 is annotated as punctate everywhere in the nucleus EXCEPT the nucleolus - and a 2024 proximity map puts it in the nucleolus
- PAF1C couples transcription to H2B ubiquitination - but the RTF1 half of that coupling is yeast-specific and contested in human cells, and PAF1C is one of the few complexes that genuinely binds the retained KMT2A fragment
- 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
- PER-485 (CVCL_W984) — the relapse half of a matched infant t(4;11) pair, and it has lost CD19
- PER-490 (CVCL_W986) — a KMT2A::AFF1 B-ALL line from a nine-day-old infant
- PER-494 (CVCL_A8JU) — infant t(4;11;7) line, and the one whose AFF1 was never demonstrated
- PER-785 (CVCL_IZ03) — infant t(4;11) line from a child who survived
- Phase-2 dossier: the fusion junction - a negative feasibility finding, with the one surviving modality named
- Phase-2 dossier: the LEDGF/PSIP1 IBD - the best therapeutic index in the interactome, a solved structure, two hotspot residues, and three compounds in the world
- PHD3 reading H3K4me3: Kd 4.3 uM for the PHD3-bromo cassette, 30 uM for PHD3 alone, two co-crystals - and the whole module is thrown away by the breakpoint
- PHGDH (O43175) - the largest menin-SELECTIVE fall in the whole serine panel, and the least essential gene in it
- PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A
- 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
- PML nuclear bodies and PML::RARA — the best-worked case of a fusion destroying a nuclear compartment, and what it actually predicts for KMT2A
- PML::RARA, t(15;17)(q24;q21)
- Ponte-di-Legno non-infant KMT2A-r ALL (n=629): 5-year EFS spans 41.7% to 91.2% across partner-by-lineage cells
- PPIE (CyP33) — the off-switch the fusion throws away, and the reason PHD3 reinsertion kills transformation
- PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion
- 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
- 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
- PRMT5 - the type II arginine methyltransferase this graph has reached for sixteen times, whose mark on H3R2 RECRUITS WDR5 to chromatin
- 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
- Programmed DNA breaks - V(D)J and class switching - and the verdict on whether either one breaks KMT2A
- 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
- 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
- Proximity-labelling map of KMT2A::AFF1 — the experiment nobody has run in twenty years of interactome work
- PSIP1 / LEDGF p75 — the tether with the best therapeutic index in the whole interactome
- PTBP1 — the strongest RNA-layer dependency in KMT2A-rearranged lines, found by a domain-focused screen and missed by this beat's own gene panel
- 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
- Put both fusion proteins in the same cell and you get something neither produces alone
- 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
- Put the same fusion in two cell types and degrade it, rather than cutting the gene
- RAG off-target activity: the dominant mutator in ETV6::RUNX1 ALL, and probably not the cause of KMT2A fusions
- Raise a KMT2A::AFF1 junction-specific monoclonal by the published TEL 6F2 protocol - rat immunisation with a junction peptide, ELISA and western screen, then a ChIP test against the wild-type-parent controls that the ETV6::RUNX1 campaign never ran
- Ranked against four fusion families, the KMT2A acetylation site is the only candidate with no evidence on the fusion at all - and the strongest argument for it is one nobody has made
- RBBP5 — a WRAD subunit that binds the one part of KMT2A every fusion throws away
- RBBP5: the thinnest fusion literature of the four subunits, and one chromatin datum
- Re-founding the address argument: the CXXC domain cannot specify a location at any affinity, and a tighter one would be worse
- Re-measured against IntAct the interactome is 103/217 (47.5%) covered, up from 41.0%, and the read queue is now ZERO - no partner with two publications or two baits lacks an entry, so the instrument's own ranking criterion has stopped selecting anything. It was also persisting the list of partners that DO have entries while counting and discarding the 105 that do not, which is the exact defect cycle 57 fixed for the other list
- Redesign: the proximity-labelling map of KMT2A::AFF1 cannot be controlled with the wild-type allele - it has to be controlled with time
- REFUTED IN THE CYCLE IT WAS WRITTEN - the proposal that fusion-driven and normal-tissue-clean surface antigens are disjoint in KMT2A::AFF1 because of what the fusion's output programme is; an expression-matched permutation says it is the base rate
- RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin
- Repeat the H3K79 partition in a human KMT2A::AFF1 line: menin inhibition and MLLT10 knockout, side by side with a KMT2A::MLLT3 line
- Retained fetal programme — the infant-versus-adult stem cell difference, and the reason KMT2A::AFF1 needs no second mutation
- RNA-binding proteins set how much KMT2A::AFF1 protein a cell makes from its own fusion transcript
- RNA-targeting the fusion transcript: verdict THE LEAST HOPELESS of the three fusion-level routes, blocked by delivery rather than by biology
- 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
- 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
- RS4;11 - the human KMT2A::AFF1 index-fusion line - has a deposited H3K79me2 pair, a MENIN pair, an MLL1-N pair, a DOT1L pair and an input under the same menin inhibitor in GSE127507. Every track needed to run this beat's test on the index fusion exists. The download is 1.99 GB measured by HEAD request, and nobody has run it.
- RS4;11 (CVCL_0093) — an ADULT KMT2A::AFF1 line, MSI-high, carrying NSD2 E1099K
- RTF1 — the PAF1C subunit the graph was missing, on a complex that does bind the retained KMT2A fragment
- Run a fusion-specific and a total-AFF1 readout side by side in the same KMT2A::AFF1 nuclei, and report the two target sets rather than one
- RUNX1 — activated by KMT2A::AFF1 and then bound by the reciprocal fusion, in the one published two-oncoprotein circuit in t(4;11)
- RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22)
- 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
- S1PR4 - the third parenchymally clean surface protein in the screen, a leukocyte-restricted GPCR, and not fusion-specific either
- 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
- SCMC-L1 (CVCL_7125) — a four-month-old's KMT2A::AFF1 line carrying NSD2 E1099K
- 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
- Scott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug
- SEC — the AFF1/AFF4-scaffolded super elongation complex, the particle KMT2A::AFF1 is a permanent subunit of
- SEM (CVCL_0095) — the workhorse, from a five-year-old, and microsatellite unstable
- SEM, the standard t(4;11) model line, has zero signal at IRX1 — every model of this disease is a model of one subgroup
- Separate ncBAF from canonical BAF in KMT2A-rearranged cells: paired degron, paralogue-pair CRISPR, and complex-resolved CUT&RUN
- Separate positioning from catalysis: an ASH2L mutant that keeps RBBP5 and loses DPY30
- Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise?
- SESN2 / sestrin-2 (P58004) - the ISR's exit into mTORC1: a leucine sensor that falls 1.4 log2 under either inhibitor, and the one panel member with a real structural record
- 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
- SETD2 (Q9BYW2) - the H3K36 trimethyltransferase that binds all seven MLL fusions, and the only one of them with a published KMT2A::AFF1 dependency test
- Settle the monocytic confound isogenically: degrade the fusion, read haem-gene dependency before lineage has time to move
- Settle the WRAD question: tagged co-IP plus degron-timed proximity across three fusion classes
- Severability (contract law) — what survives when a clause is struck, and what survives a KMT2A break
- 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
- 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
- SGK1 / SGK (O00141) - a MENIN-SELECTIVE upregulated kinase, a druggable AGC family member, and the panel's worst platform disagreement
- SHMT2 (P34897) - the mitochondrial one-carbon step, and the paralogue that rises while it falls is why its loss may not matter
- SIAH1 — the E3 ligase that degrades AFF1, and that the reciprocal AF4::KMT2A fusion escapes
- SIAH2 — the second AFF1 E3 ligase, reported only alongside SIAH1 and never separated from it
- Silmitasertib (CX-4945) - a CKII inhibitor that works on KMT2A-rearranged leukemia by strengthening the allele the fusion does not have
- SIT1 - one of only three surface proteins in the screen that is both expressed in KMT2A::AFF1 lines and absent from normal parenchyma, and it is clean because it is leukocyte-restricted, not because it is leukaemic
- Six to twenty-four libraries in RS4;11: two DOT1L inhibitors titrated to equal spike-in-measured global H3K79me2 loss, three replicates per arm, plus the no-primary control that no public deposit contains - the smallest experiment that would convert four moderate entries in this beat into testable ones
- 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
- 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
- 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
- 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
- Spike-in-normalised menin CUT&RUN in a KMT2A::AFF1 degron line, with replicates and a PSIP1 arm
- Spike-in-normalised menin CUT&RUN with paired N- and C-terminal KMT2A antibodies in an infant KMT2A::AFF1 sample, on and off drug, in the same disease state
- SPP1 (osteopontin) - the endosteal matrix protein whose knockdown prolongs survival in MLL-AF9 mice, and the one KMT2A::AFF1-specific paper about it cannot be read
- SS18 - a SWI/SNF subunit that is itself a fusion partner in another cancer, and a lineage-independent dependency in KMT2A-rearranged lines
- 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)
- STC2 / stanniocalcin-2 (O76061) - the second largest effect in the signature (-4.40 log2), a SECRETED glycoprotein, and its localisation rests on curator inference alone
- Step 3: the G-banded karyotype and t(4;11)(q21;q23)
- Step 4: the split-signal FISH nucleus - one fusion, one green, one red
- Step 5: molecular confirmation and naming the partner
- Subclonal cooperating lesions lost at relapse - what was actually measured, and why 'lost' is the wrong word
- SUPT16H (SPT16) - the large FACT subunit: pan-essential, an anti-dependency in KMT2A-rearranged lines, and drugged in MLL-r leukaemia by a compound that works through p53
- 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'
- Tag the endogenous KMT2A::AFF1 allele in RS4;11 and ChIP the tag with and without VTP-50469 alongside MENIN and MLL1-N in the same chromatin - the one experiment that converts every occupancy claim in this literature from a reagent statement into a fusion statement
- Targeted PRM for the KMT2A::AFF1 junction peptide - the experiment that makes every other attribution claim testable
- TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes
- Taspase1 and its two KMT2A cleavage sites: an enzyme-substrate interface with four apo structures, one co-crystal with a small molecule, and no structure with MLL at all
- TB920488, the other HOXA-negative IRX1-negative blast, has the highest GMP-over-B-lineage ratio of any B-lineage sample in the deposit - and it fails both the matched null and the N-over-C test
- 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
- Ten affinity measurements for this contact and not one uses a fusion protein, full-length KMT2A or a nucleosome
- TERT — telomerase, switched on by the index fusion through HOXA7
- The 'infant ALL' PDX panel with four KMT2A::AFF1 models — one of which the full text calls adult
- The 'raw library promoter mean' that two cycles treated as library coverage tracks the in-promoter fragment FRACTION at Spearman +0.993 and true sequencing depth at only +0.292, and the oncoprotein share correlates with true depth at -0.255
- The 17-promoter AFF1-only recurrent core is not more recurrence than a label permutation of the same matrix gives
- 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 332-promoter AFF1-only set is BELOW the count a random eight-sample arm produces (null 425)
- The AFF-family N-terminus on cyclin T1: Kd 10 nM, a 2.94 A crystal, and every number in it measured on AFF4 rather than on AFF1
- The age confound: a partner arm and an age arm are nearly the same arm
- The B-ALL and the AML of one infant share no more fusion-occupied promoters than two unrelated infants do - lineage, not patient identity, sets where KMT2A::AFF1 sits
- The CD24-positive pre-leukaemic state — what the index fusion makes before it makes leukaemia
- The clustered PHD fingers (KMT2A aa 1416-1640) are a chromatin-targeting module and the canonical t(4;11) junction removes them by ten residues
- 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 decisive experiment: acute degron removal of IGF2BP3, IGF2BP2 and both, read on self-renewal and xenograft initiation rather than bulk dropout
- 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 differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia
- The endogenous MLL-AF4 localisation experiment was unattributable, not negative: an anti-AF4 polyclonal in a t(4;11) cell images mostly wild-type AF4
- The experiment nobody has done: an epitope tag knocked into the endogenous KMT2A fusion allele in a patient-derived line
- The experiment this beat could not do: an epitope-tagged KMT2A::AFF1 ChIP with a Drosophila spike-in, in a human infant-derived B-lineage line, at three replicates and two menin-inhibitor exposures - the design that would turn a within-sample ranking into an absolute occupancy measurement
- The fusion begins at AFF1 residue 347 and the cyclin T1-binding sequence ends at 308, so KMT2A::AFF1 is the one AFF-family protein that cannot enter the reservoir
- The fusion junction itself as a small-molecule target: a candid verdict
- The fusion-biased peak at the AFF1 locus fires in 23 of 27 samples across all six partners, so it is not the fusion visiting its own partner
- 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
- The G1 state in KMT2A-rearranged leukaemia — where CDK6 does a job that is not about the cell cycle at all
- The imports that were never necessary: H3K79 methylation in KMT2A::AFF1 has its own literature, and this graph barely cites it
- The index fusion DISCARDS the SIAH degron: the junction is at AFF1 residue 347, the degron is at human 282-304, and three entries had it the other way because they measured a murine motif against an exon-numbering junction
- The infant breakpoint mutilates the reciprocal protein's first PHD finger - so 'the reciprocal product' is at least two different proteins
- The innate-immune-rewired state — LAMP-5 is a direct fusion target that routes signalling away from interferon and toward NF-kB, and the cell depends on that routing
- The interactome tail is orderable after all, just not by evidence: 62 of the 96 unwritten partners are already DISCUSSED somewhere in this corpus and need only promoting to entries, while 34 have never been read at all. Two cycles looked for a priority order in evidence strength and found none, because the ordering that exists is over how much work is left, not over how good the evidence is
- 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
- 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
- The KMT2A::AFF1 oncoprotein-target promoter set is a fusion-level property, and patient identity adds nothing measurable on top of it
- The KOCL series (CVCL_3993, CVCL_6867, CVCL_3994, CVCL_3995) — four Japanese infant KMT2A::AFF1 lines, all under one year
- 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 little elongation complex (ELL + ICE1 + ICE2 + ZC3H8) — the other place ELL works, and why ELL's pan-essentiality is probably not about the fusion
- The lymphoid-restricted DAXX dependency survives three nulls and two comparator restrictions - and ATRX, MEN1 and DOT1L do not survive the same test in the same lines
- 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 menin interface cannot be what decides where KMT2A::AFF1 sits: within one patient the fusion's target promoters were almost entirely replaced while the menin-binding motif was unchanged
- The menin interface is a requirement of 5'-KMT2A fusions in haematopoiesis, not of KMT2A rearrangement as such - and a solid tumour has been quietly proving it for six years
- The menin interface is identical in all 27 of these patients and the amount of chromatin their oncoproteins occupy differs by up to two orders of magnitude - so the interface can be a permission for binding but cannot be what sets how much binding happens
- The menin that matters in an infant KMT2A-rearranged leukaemia is the menin on the fusion, and the N-minus-C antibody difference can measure it in any patient sample without a tag
- The missing reagent is a spike-in, not a better statistic: a spike-in-normalised H3K4me3, H3K79me2 and H3K27me3 ChIP-seq at 72 h of a clinical menin inhibitor in a KMT2A-rearranged human line, which is the only design that can tell a genuine genome-wide mark redistribution from the compositional shadow of a peak-localised change
- 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 MLL3/4-UTX switch fails to throw — menin inhibition kills by turning something ON, and cells that cannot turn it on survive
- The MT/BCB domain, Q03164 1147-1244: the CXXC fold plus a 41-residue basic tail nobody has measured on its own
- 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 nuclear pore and NUP98 fusions — a fusion that takes a pore protein's disordered repeats off the pore and builds nuclear droplets with them
- The nucleolus — the one compartment with direct published images of a KMT2A fusion inside it
- 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
- The one experiment that would close the SUV39H1 arm of this graph's H3K9 argument: CST #8729S CUT&RUN in a CD34+ progenitor and in SEM or RS4;11, with an IgG arm and a SUV39H1-degron arm that neither existing deposit has - because after this cycle the enzyme has been measured in exactly two human cell types and neither is a blood cell
- The one experiment that would close this beat: MEN1 and DOT1L ChIP in RS4;11 (KMT2A::AFF1) under DMSO, a menin inhibitor and a target-engaging DOT1L inhibitor, with Drosophila spike-in and two replicates per arm - about 24 libraries, and the depositing lab already runs every component of it
- The other half of the break: what is actually known about the AFF1 breakpoint region, and the negative-control gene nobody cites
- The panobinostat H2Bub result is SEM and KOPN8 against a REH comparator: three human lines, two KMT2A partners, one non-KMT2A control
- The partner, not the site, is what could make a retained KMT2A modification fusion-specific - the AML1-ETO mechanism asked of KMT2A::AFF1
- The partner's deubiquitinase domain is what lets a PHD-retaining KMT2A fusion survive and transform
- The pluripotent stem-cell route has failed from both ends, and the failures are informative
- The prey-only interactome is 36.3% written, not 0% - the census, by identity, of all 212 human prey-only partners of the six core proteins
- 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
- The reciprocal ChIP: is chromatin-bound XPO1 present in a KMT2A-rearranged cell, and does a menin inhibitor move it?
- The reciprocal fusion (AFF1::KMT2A and friends): a second oncoprotein that opens chromatin for the first
- 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
- The soluble-nucleoplasm versus chromatin-bound axis - the one localisation readout that keeps a size dimension, and nobody has run it on a KMT2A fusion
- The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell
- The taspase-1 N/C antibody control separates fusion-occupied from wild-type KMT2A promoters in every primary infant sample, and it is the C-terminal arm that does the work while being the less reproducible arm
- The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3
- 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
- The two t(4;11) products split AFF1 exactly at the P-TEFb-binding module, and the elongation half goes to the reciprocal
- The two TARGET B-ALL studies in cBioPortal are 868 of the same patients assayed twice, so joining them DOES answer the question I had just written off as unanswerable: all four ARID1A-mutant B-ALL patients are definitively KMT2A-negative, three of them with truncating calls. The answer is zero of three - and at a 2.7% KMT2A-positive rate an empty overlap has probability 0.92, so it is an upper bound and not a finding
- The unnamed KMT2A-rearranged B-ALL line is SEM, and the deposition says KMT2A::AFF1 in a genotype field
- 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
- Thomas Milne (MRC WIMM, Oxford) — MLL-AF4 target biology, enhancer architecture and PROM1/CD133
- Three addresses, one output: what SET::NUP214 actually does to the menin-interface hypothesis, and why it is a weaker test than CALM-AF10
- 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
- TNF — the only NF-kB-activating ligand with real KMT2A::AFF1 B-ALL evidence, and the evidence says the blasts are RESISTANT to it
- TOP2A - the proliferation isoform, the one the drugs are actually measured against, and the only one with a germline association in this disease
- Topoisomerase II cleavage and TOP2 poisons as a source of KMT2A breaks
- TPR / Megator (P12270) - the nuclear-basket nucleoporin that builds heterochromatin exclusion zones, in the pan-MLL-fusion core
- TRIB3 / TRB3 (Q96RU7) - a pseudokinase that is the ISR's own brake, falls 3.1 log2 under either inhibitor, and has a published physical link to the MLL complex in the wrong tissue
- 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
- Twin concordance: near-total for infant KMT2A-rearranged leukaemia, about 5% for childhood ALL overall
- Two clones, two antibodies: a four-month-old with refractory KMT2A::AFF1 mixed-phenotype leukaemia treated with blinatumomab and gemtuzumab together
- Two groups invoke LIN28B to explain the SAME epidemiological fact in OPPOSITE directions - and neither claim is the one this graph has been repeating
- 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
- 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
- UBTF tandem duplications INVENT an export signal, and that invented signal is what puts the protein on chromatin - the cleanest proof the XPO1 address is real
- USP22 — a KMT2A-rearranged dependency that works through MEIS1 protein stability, and is not an interactor of the fusion
- 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
- Valemetostat - an approved dual EZH1/EZH2 inhibitor that has already worked in an MLL-AF4 xenograft, in a disease nobody has enrolled it in
- Venetoclax in KMT2A-rearranged leukemia — the apoptotic partner every other drug needs
- 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
- VIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon
- 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
- WDR5 WIN site and KMT2A Arg3765: measured at 1.7 uM, three co-crystals, and absent from every leukaemic fusion - plus the MLL3 peptide that binds it 51-fold tighter
- WDR5: an established wild-type KMT2A contact, and no fusion contact ever measured
- WEE1 - the one checkpoint target with a KMT2A::AFF1-specific result, and the paper that also found the escape route
- What could refute the menin-interface bet, restated after the provenance audit: three tests, none of which is about menin binding
- What is a fusion gene?
- What is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule
- What the paralogues' disease biology says about AFF1: the AFF family shares one SIAH degron — and the index fusion DISCARDS it, because the whole degron lies in the AFF1 leader that the junction at residue 347 throws away
- Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question
- Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin
- Which partner, in which patient: KMT2A partner frequencies across six age-lineage strata
- Which repair pathway glues the fusion together: classical NHEJ vs alternative end joining
- Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it
- YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away
- 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
- ZMYND11 (BS69) - an H3.3K36me3 reader that restrains elongation, is itself the 5' partner of a chromatin-hijacking AML fusion driving HOXA/MEIS1/MYB, and whose promoter is the third-strongest MLL1-N bin in RS4;11
- ZNF384::TEX41 - the case that breaks the family's architecture: ZNF384 is the 5' partner, the 3' partner is a lncRNA, and the fusion is out of frame
- 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
Only KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3) · 103
- "Diverse models of MLL-rearranged leukaemia" is one mouse cell line: the RNF20 H2Bub requirement resolves to murine RN2 (MLL-AF9/NrasG12D)
- 756 children with 11q23/MLL-rearranged AML: 5-year EFS runs from 11% to 92% depending on the partner
- A 2026 preprint puts XPO1 upstream of the menin interface itself: XPO1 reported to stabilise menin on chromatin and menin's binding to KMT2A and KMT2A::MLLT3
- A DOT1L inhibitor, which does not touch the menin-KMT2A interface, removes 70% of the fusion's enrichment from its own strongest sites - two thirds of what a menin inhibitor removes - so fusion chromatin residency is partly downstream of H3K79 methylation rather than only of menin
- A menin inhibitor is not a fusion degron, so watching menin leave chromatin under one cannot identify what was holding it there - every model predicts the same result
- ACSL4 - a CRISPR-screen-derived, functionally validated KMT2A-selective vulnerability in myeloid disease, and a gene whose loss normally protects cells from ferroptosis
- AF9's nuclear residence is chaperone-dependent, the Hsp90 site is the SAME C-terminal region the fusion keeps, and UniProt records no cytoplasmic pool at all
- AKAP95 IDR1 co-condenses with the KMT2A N-terminal fragment - the one AKAP95 contact that lands inside the region every KMT2A fusion retains
- An anti-MLL-N antibody sees the wild-type allele and the direct fusion, and nothing else - and cannot rank them
- Anti-AF9 antibodies see three proteins, not two - and the third is an internal-promoter isoform discovered in 2025
- 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
- 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
- Asked for the first time whether a KMT2A fusion GAINS chromatin sites under a menin inhibitor: all three pre-registered criteria fire, and the set they fire on is 52 low-amplitude bins reaching 6x the genome median, 16 of them with no gene within 20 kb and 1 of 52 on a CpG island where 66% of the fusion's real sites are
- BCOR, not CBX8, is the AHD contact MLL-AF9 cannot lose - and the same two partners bind ENL far more tightly than AF9
- 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
- BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing
- CBS (P35520) - the largest fall in the whole panel (-4.07), a token that collides with Cajal bodies AND CTCF binding sites, and a germline phenotype whose hallmark is thrombosis
- CBX5 / HP1-alpha (P45973, 191 aa) - the H3K9me3 reader that recruits the writer, the writer's destroyer and the second writer; and the one member of that circuit with a published pro-leukaemic role, as part of an MLL leukaemia stem-cell programme that immortalises myeloid progenitors WITHOUT Hoxa or Meis
- CK2 phosphorylates KMT2A at T2724/S2726 to license taspase1 cleavage - and that site is in the half the fusion throws away
- DNA-PKcs phosphorylates AF9 at S395 and releases it from the super elongation complex - the only AF9 regulatory element the fusion keeps
- 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's localization record is a mouse kidney paper wearing a human label - and the one image of it in a leukaemia cell is a supporting figure a title search cannot see
- EIF2AK3 / PERK (Q9NZJ5) - the kinase whose transcript is flat under both inhibitors, whose arm IS functionally required in MLL-AF9 leukaemia stem cells, and whose common name collides with phospho-ERK
- 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
- EPHA7 is the one core member with a published KMT2A::AFF1 promoter ChIP - and this beat's own data put it second on separation while denying it to the AF9 samples
- Every human t(9;11) cell line, with every accession fetched and read back: eleven lines, ten patients, and two of them are B-ALL
- First deposit to put both drug classes on the MEN1 channel in one experiment: VTP-50469 leaves ZERO of the 19 DMSO menin peaks at 15 canonical menin-MLL target loci, while EPZ5676 keeps 14, compound 10 keeps 14 and compound 11 keeps 8 - strength-matched permutation p = 0.0003, and the zero is unchanged at every flank from 0 to 100 kb
- Four regulatory elements on AF9, and the fusion keeps exactly one - the phospho-switch that controls SEC binding
- GATAD2A / p66-alpha (Q86YP4) - the subunit that bridges NuRD's two modules, the best-ranked NuRD gene in this project's KMT2A-selectivity scan, and present in the pan-fusion interactome under MLL-AF9 but NOT the index fusion
- 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
- GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way
- H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of
- 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
- 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
- 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
- HNF4A - a liver and pancreas nuclear receptor acting as the metabolic effector of TIFAB in KMT2A::MLLT3 AML, on a single paper
- 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
- Import class 1: murine MLL-AF9 myeloid transformation, the field's default assay and this graph's largest single import
- In murine MLL-AF9, H3K79me2's response to a menin inhibitor runs 0.586 / 0.819 / 0.928 / 1.187 across the four eviction-depth quartiles of the fusion's own top-0.1% sites - Spearman -1.000, span 0.6005, the largest of any mark measured in these bins except H3K27me3 - while the aggregate over the same 1,228 bins is a single unremarkable 0.8156
- IntAct curates 47 interactions against engineered MLL fusion proteins, and every accession-keyed query in this project is blind to all of them - while its PSICQUIC mirror stops at 2024
- JD-PI95 - a genetically encoded bridging peptide that drags AKAP95 to HSP70 and dissolves its condensates, with in vivo activity in THP-1
- 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
- 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
- KMT2A-rearranged acute myeloid leukaemia in children and infants
- KMT2A-rearranged AML is two diseases on the phosphorylation layer, and DOT1L phosphorylation is one of the things that separates them
- KMT2A-rearranged or NPM1-mutant? Both, in separate arms: WT-MA9 mouse, MOLM13, OCI-AML3, and two patients on AUGMENT-101
- 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
- KMT2A::MLLT3 / t(9;11): the best-known partner prognosis claim, and the three cohorts that did not reproduce it
- KMT2A::MLLT3 across 612 genotyped patients: myeloid at every age, but 248 of them have ALL, and 157 of those are infants
- Knock S395A into the MLLT3 half of a KMT2A::MLLT3 model and ask whether it becomes chemotherapy-resistant
- KOPB-26 (CVCL_7972): a t(9;11) B-ALL line from a 13-month-old, and the model for 42% of this partner's patients that nobody uses
- 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)
- MECOM (EVI1) - a cell-of-origin memory that MLL-AF9 maintains but cannot install, present in about 43% of MLL-rearranged AML and marking the chemoresistant half
- 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
- Menin does not outlast the fusion under revumenib in primary infant material - 0.586 against 0.485 at oncoprotein peaks, a ratio of 1.21 against a pre-registered threshold of 1.5 - so the fusion-independent menin plateau seen after a degron does not reproduce here
- Menin loses half its promoter signal where the fusion sat, and nothing where it did not
- Menin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled
- MLL-AF9 leukaemia destroys the nerves that run its own niche — a mechanism class this graph had nothing on
- 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 is the commonest partner in therapy-induced KMT2A leukaemia: 49 of 142, and 47 of those are t-AML
- MLLT3 runs normal stem-cell self-renewal and is required in essentially no leukaemia line — the inverted case
- MOF/KAT8 is required by both KMT2A::MLLT3 and NUP98::HOXA9 — which is why it is the wrong kind of convergence
- MOLM13 (KMT2A::MLLT3) is the only line in GSE127507 with a matched input in BOTH conditions, and it gives the one differential-input-controlled measurement in the series - MLL1-N occupancy at its own top 0.1% of bins is unchanged (share ratio 0.9438, input 0.9542, input-corrected 0.9891) with ZERO gained bins genome-wide, while menin retains only 13.0% of its own top windows
- 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
- Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1
- PPP1R15A / GADD34 (O75807) - the eIF2alpha phosphatase adaptor, and KMT2A fusion proteins were shown to BIND it and block its apoptosis in 1999, a paper this graph has never cited
- PROM1 occupancy tracks HOXA at +0.93 in KMT2A::AFF1 and not at all elsewhere; it is near-absent in KMT2A-AF9 and -AFDN despite high HOXA
- Removing the fusion is a transcription event first and a chromatin event later, and the gap is enormous: nascent transcription changes within 15 minutes, while genome-wide RNA Pol II peak calls are 99.6% retained at 3 hours and not one active histone mark loses a peak call by 24 hours - the fusion's immediate job is licensing elongation, not building a chromatin landscape
- Repairing 85 defective citation blocks, and the finding that the queue's own numbers were wrong in three directions at once
- Scored against the same DMSO in the same batch, degrading the fusion leaves 1.0% of its chromatin sites, the DOT1L+menin combination leaves 10.7%, the menin inhibitor alone leaves 51.7% and the DOT1L inhibitor alone 75.5% - and in a second independent batch the menin inhibitor again beats the DOT1L inhibitor on the fusion's own channel
- SIN3A (Q96ST3) - the scaffold of the OTHER HDAC1/2 corepressor complex, a 5' fusion partner in infant B-ALL and in myelodysplasia, and present in three MLL-fusion AP-MS columns but not the index fusion's
- Skin first, blood later: a three-day-old referred for purple spots, with KMT2A::MLLT3 neonatal ALL
- SMC3 - the cohesin ATPase arm, the only subunit whose partial loss has been tested directly against a KMT2A fusion, and it was tolerated
- 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
- Spliced KMT2A fusions: breaks upstream of the partner's exon 1, and the reciprocal-free natural experiment
- Summit containment passes the positive control that the bin-overlap measure failed, in all three HA batches
- 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
- t(9;11) is the reciprocal-POSITIVE arm: 2 of 612 patients are spliced, against 241 of 460 for t(11;19)
- t(9;11): the reciprocal product is made, is engineered into every genome-editing model, and has never been separately tested
- The AF9 acetylation arm: PCAF at K339, HDAC5 gated by CaMKII - a kinase-controlled switch the fusion throws away
- The AHD inhibitor's deposited arm is MOLM-13 and its in vivo arm is nowhere: a half-resolution that names the limit exactly
- The chromatin exchange at a menin-inhibited fusion site, measured in one experiment: H2AK119ub and H3K27me3 in, H3K4me3 out, in proportion to how much fusion left - and PCGF1 loss attenuates the in-fill without abolishing it
- The CSF1R-positive fetal lymphoid-primed multipotent progenitor — a fetal-restricted subset of LMPPs that makes AML rather than ALL when KMT2A::MLLT3 is switched on, and exists in human embryos
- 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 four-way ordering given a second cell line: menin, DOT1L and the MLL1-N channel reproduce between KMT2A::AFF1 and KMT2A::MLLT3 to within 0.04 of a share ratio, and H3K79me2 - the one channel the ordering was built around - diverges by 0.21 to 0.30 and changes places with MLL1-N
- The GSE260742 H2AK119ub pair that shares a processing state - rep2 against rep3, both bare `.tdf` - is not an unconfounded replicate pair: rep3 was submitted 2024-10-01 and rep2 2024-03-03, through a different file-naming pipeline. No pairing in this deposit isolates replicate variance alone.
- The KMT2A breakpoint cluster region: an 8.3 kb stretch built to break
- The KMT2A::MLLT3 chimeric protein: what survives the join on each side, in residue numbers - and the four AF9 modules that do not
- The Mediator/BET deposition is 48 of 48 mouse MLL-AF9/NrasG12D samples: resolving the KMT2A status behind the MED23 verdict
- The menin inhibitor removes three-quarters of the fusion from its own promoters, replicated in two batches
- The positive control this corpus has never had: degrading MLL::AF9 clears its own tag from 93-97% of its strongest chromatin sites within 3 hours, and two INDEPENDENT sequencing batches agree to within 4.6 points - the first technical noise floor ever measured for a ChIP eviction comparison in this project
- 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
- The same-condition H2AK119ub noise floor in GSE260742 spans twentyfold across the deposit's three experimental arms - D1 |R-1| of 1.89% in the PCGF1-KO clone, 10.49% in the non-targeting control and 37.04% in the MLLAF9 Control arm - at one mark, one lab, one pairing shape and one external stratifier. A single same-condition floor for this deposit does not exist.
- 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 stratification passes its own positive control: the fusion tag separates the two strata 62-fold
- The strongest published case that condensates are load-bearing in KMT2A-fusion leukemia — and it is AKAP95, not AFF1
- The unnamed AML lines are NB4 and THP-1 - and NB4 is not KMT2A-rearranged at all
- The unnamed osteolineage Cre is Prx1-Cre, which is not osteoblast-restricted - and that changes what the negative result means
- THP-1 (CVCL_0006): the default KMT2A::MLLT3 line, from a one-year-old, carrying NRAS G12D and a TP53 frameshift
- VTP-50469 - the preclinical menin-KMT2A interface inhibitor that almost every chromatin experiment in this field actually used, and which had no entry of its own in this graph
- Where KMT2A::MLLT3 sits in the nucleus: two papers, both overexpression, both from before 2005 - and the fusion carries no AF9 import signal
- Where t(9;11) actually breaks inside MLLT3: 98.4% downstream of exon 4, and the two patients in 442 who kept the reader
KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
In this leukemia a gene called KMT2A snaps in half and glues itself to a gene called AFF1, and the hybrid protein that results sits on the genes a blood cell needs to grow up and jams them permanently switched on. It is the commonest cause of leukemia in babies under one year old, and only about half of those babies are cured, because unlike the kinase fusions this protein has no enzyme pocket for a drug to plug.
- sourced claims
- 8
- counter-arguments
- 9
- distinct sources
- 8 (7 papers)
- connections
- 569
established 5strong 2moderate 1
related to · 308
- 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 · Gene
- Experiment: combinatorial dose-titration of the HOXA9/MEIS1 program to find its minimal cut set · Experiment
- Severability (contract law) — what survives when a clause is struck, and what survives a KMT2A break · Analogy
- Hypothesis: the reciprocal AFF1::KMT2A product protects only when it is structurally complete, so its prognostic effect is a breakpoint class in disguise · Hypothesis
- Which partner, in which patient: KMT2A partner frequencies across six age-lineage strata · Breakpoint
- Separation-of-function test: does KMT2A::AFF1 need its C-terminal homology domain to dimerise? · Experiment
- KMT2A::AFF1 oligomerises through the retained AFF1 CHD, putting the commonest fusion in the oligomerisation class · Hypothesis
- Cyclophosphamide - where the KMT2A literature reports two different activated oxazaphosphorines and only one of them is this drug's metabolite · Drug
- Programmed DNA breaks - V(D)J and class switching - and the verdict on whether either one breaks KMT2A · Explainer
- Experiment: measure KMT2A-AFF1 spatial proximity in the human fetal progenitor, in the cell and at the time the translocation actually happens · Experiment
- The G1 state in KMT2A-rearranged leukaemia — where CDK6 does a job that is not about the cell cycle at all · Cell state
- Where KMT2A and its fusions sit inside the nucleus — SNL1/SNL2, nuclear speckles and the condensate question · Mechanism
- Is KMT2A::AFF1 leukemia epithelial or endothelial? No — it is haematopoietic. But the question is a good one · Explainer
- 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 · Mechanism
- Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it · Explainer
- KMT2A::AFDN (MLL-AF6), t(6;11)(q27;q23) · Fusion
- Mechanism class 1 — chromatin and elongation hijack (KMT2A-r, NUP98-r) · Mechanism
- Hypothesis — the menin lesson generalises: every non-enzymatic fusion has an obligate partner interface that is more druggable than the fusion · Hypothesis
- NUP98 fusions share the menin dependency (confirmed preclinically) — and the partner-supplied reader/writer module is not why · Hypothesis
- Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents · Explainer
- The reciprocal ChIP: is chromatin-bound XPO1 present in a KMT2A-rearranged cell, and does a menin inhibitor move it? · Experiment
- KMT2A rearrangement creates a requirement for the FA ubiquitin-transfer module — the claim, its prior, and the four results that would kill it · Hypothesis
- No KMT2A fusion junction peptide has ever been reported - the one measurement that would prove the protein exists has not been published · Analysis
- Anti-AFF1 antibodies: attributable on a gel, not attributable in a microscope, and the classic localisation result shows exactly why · Explainer
- The experiment nobody has done: an epitope tag knocked into the endogenous KMT2A fusion allele in a patient-derived line · Explainer
- Bounded unreadable: the only affinity purification of a SET-retaining KMT2A-derived fusion complex fails all four routes, and the molecule is the reciprocal product · Analysis
- Experiment: does MLL-AF4 transform a staged fetal progenitor when it cannot transform cord blood? · Experiment
- Experiment: long-hold degron depletion of endogenous KMT2A::AFF1, to ask whether the leukaemic program recovers without the fusion · Experiment
- In-utero origin, proven: clonotypic KMT2A::AFF1 junctions found in the patient's own newborn blood spot · Mechanism
- Twin concordance: near-total for infant KMT2A-rearranged leukaemia, about 5% for childhood ALL overall · Epidemiology
- Are the fusions temporary? No: the KMT2A fusion is the one thing that does not change between diagnosis and relapse · Mechanism
- Does KMT2A::AFF1 change histone turnover at its target genes, or does it read a chromatin state it did not make? · Hypothesis
- PAF1C couples transcription to H2B ubiquitination - but the RTF1 half of that coupling is yeast-specific and contested in human cells, and PAF1C is one of the few complexes that genuinely binds the retained KMT2A fragment · Mechanism
- 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 · Gene
- KMT2A-rearranged acute leukemia across all ages: infants are 4% of it · Epidemiology
- PER-490 (CVCL_W986) — a KMT2A::AFF1 B-ALL line from a nine-day-old infant · Explainer
- PER-494 (CVCL_A8JU) — infant t(4;11;7) line, and the one whose AFF1 was never demonstrated · Explainer
- PER-485 (CVCL_W984) — the relapse half of a matched infant t(4;11) pair, and it has lost CD19 · Explainer
- PER-785 (CVCL_IZ03) — infant t(4;11) line from a child who survived · Explainer
- ALL-PO (CVCL_1069) — an infant KMT2A::AFF1 line that is already in DepMap and has never been screened · Explainer
- BLIN-3 (CVCL_QW47) — a three-month-old's KMT2A::AFF1 line used to show the pro-B to pre-B block can be pushed · Explainer
- SCMC-L1 (CVCL_7125) — a four-month-old's KMT2A::AFF1 line carrying NSD2 E1099K · Explainer
- The KOCL series (CVCL_3993, CVCL_6867, CVCL_3994, CVCL_3995) — four Japanese infant KMT2A::AFF1 lines, all under one year · Explainer
- SEM (CVCL_0095) — the workhorse, from a five-year-old, and microsatellite unstable · Explainer
- RS4;11 (CVCL_0093) — an ADULT KMT2A::AFF1 line, MSI-high, carrying NSD2 E1099K · Explainer
- MV4-11 (CVCL_0064) — KMT2A::AFF1, yes, but a ten-year-old's acute monocytic leukaemia with FLT3-ITD · Explainer
- The 'infant ALL' PDX panel with four KMT2A::AFF1 models — one of which the full text calls adult · Explainer
- CRISPR-engineered t(4;11) in human fetal liver — the only model that reproduces infant-specific biology · Explainer
- Mll-AF4 mouse genetics — B-lineage tumours, long latency, and never infant pro-B ALL · Explainer
- MLL fused to MURINE Af4 in human CD34+ cells — the model that works, and the swap that makes it work · Explainer
- The pluripotent stem-cell route has failed from both ends, and the failures are informative · Explainer
- IMSUTi002-A-2 (CVCL_C9HE) — a doxycycline-inducible KMT2A::AFF1 iPSC line, and the isogenic design nobody in this graph has used · Explainer
- HCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind · Protein
- PPIE (CyP33) — the off-switch the fusion throws away, and the reason PHD3 reinsertion kills transformation · Protein
- KAT8 (MOF) — a genuine KMT2A partner that binds the half of KMT2A the fusion discards · Protein
- CREBBP (CBP) — binds the KMT2A transactivation domain, which no fusion keeps · Protein
- USP22 — a KMT2A-rearranged dependency that works through MEIS1 protein stability, and is not an interactor of the fusion · Protein
- SIAH1 — the E3 ligase that degrades AFF1, and that the reciprocal AF4::KMT2A fusion escapes · Protein
- SIAH2 — the second AFF1 E3 ligase, reported only alongside SIAH1 and never separated from it · Protein
- MLLT6 (AF17) — the fourth KMT2A fusion partner inside DotCom, and the only one no cell needs · Protein
- 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 · Protein
- 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 · Protein
- RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once · Protein
- 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 · Protein
- 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 · Protein
- PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion · Protein
- SUPT5H (SPT5) — the pausing factor the KMT2A field has never studied, and the counted absence that undercuts 'the fusion hijacks pause release' · Protein
- SUPT4H1 (SPT4) — zero papers linking it to KMT2A, and the 138th most KMT2A-selective gene out of 17,728 · Protein
- 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 · Protein
- EAF1 — the interactor with an actual subnuclear phenotype: an MLL fusion evicts it from Cajal bodies, and the bodies themselves fall apart · Protein
- EAF2 (U19) — the EAF paralogue whose ELL-binding domain is a mapped tumour-suppressor module, described entirely in prostate cancer · Protein
- 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 · Protein
- ICE2 — the fourth LEC subunit, the one with no assigned step, no structure, and no leukaemia literature · Protein
- EP300 — the acetyltransferase whose paralogue split is the finding: p300 is the 108th most KMT2A-selective gene, CBP is the 16,950th · Protein
- KDM1A (LSD1) — acts at the loci the fusion binds, spares normal stem cells, and still has never been shown to touch the fusion protein · Protein
- MYB — rank 17 of 17,728 for KMT2A selectivity, and the only node in this beat where partial, transient suppression eradicated leukaemia without stopping normal blood production · Protein
- 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 · Protein
- SUPT16H (SPT16) - the large FACT subunit: pan-essential, an anti-dependency in KMT2A-rearranged lines, and drugged in MLL-r leukaemia by a compound that works through p53 · Protein
- 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) · Protein
- FACT (SPT16-SSRP1) - the chromatin arm of transcription elongation, and a clean negative result for the KMT2A::AFF1 interactome · Protein
- 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 · Protein
- Does WDR5 move between complexes? An acute KANSL1 degron with WDR5 co-IP, WDR5 CUT&RUN and H4K5/K8/K16ac readout in a KMT2A-rearranged line · Experiment
- 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 · Analysis
- HNRNPA2B1 — the panel's strongest KMT2A-selective RNA-layer gene after PTBP1, with ZERO records against MLL or KMT2A · Gene
- WDR5 WIN site and KMT2A Arg3765: measured at 1.7 uM, three co-crystals, and absent from every leukaemic fusion - plus the MLL3 peptide that binds it 51-fold tighter · Interface
- The AFF-family N-terminus on cyclin T1: Kd 10 nM, a 2.94 A crystal, and every number in it measured on AFF4 rather than on AFF1 · Interface
- Taspase1 and its two KMT2A cleavage sites: an enzyme-substrate interface with four apo structures, one co-crystal with a small molecule, and no structure with MLL at all · Interface
- PHD3 reading H3K4me3: Kd 4.3 uM for the PHD3-bromo cassette, 30 uM for PHD3 alone, two co-crystals - and the whole module is thrown away by the breakpoint · Interface
- 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 · Interface
- Half this graph's claims are unopposed; these are the ones that matter · Analysis
- 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 · Analysis
- 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 · Analysis
- KMT2A::AFF1 retains THD2 by position, so the HBO1 contact can apply to it — but the paper that established that contact tested MLL-ELL, MLL-AF6 and MLL-AF10, never the index fusion · Analysis
- 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 · Analysis
- The reciprocal fusion (AFF1::KMT2A and friends): a second oncoprotein that opens chromatin for the first · Mechanism
- 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 · Hypothesis
- Hypothesis: transfer-RNA and ribosome biology is a genuinely empty cell in KMT2A-rearranged leukemia, and translational capacity may be the unmeasured dependency · Hypothesis
- In St. Jude paediatric AML, 2 of the 6 ARID1A-mutant cases are KMT2A-rearranged and BOTH ARID1A mutations are TRUNCATING frameshifts in KMT2A::MLLT10 cases - so the exact combination cycle 86 showed the ARID1B dependency is confined to DOES occur in patients, and cycle 88's empty DepMap intersection is a cell-line sampling artefact rather than a fact about the disease. The paediatric ALL cohort returned zero ARID1A mutations, which is panel coverage and not biology · Analysis
- The two TARGET B-ALL studies in cBioPortal are 868 of the same patients assayed twice, so joining them DOES answer the question I had just written off as unanswerable: all four ARID1A-mutant B-ALL patients are definitively KMT2A-negative, three of them with truncating calls. The answer is zero of three - and at a 2.7% KMT2A-positive rate an empty overlap has probability 0.92, so it is an upper bound and not a finding · Analysis
- Re-measured against IntAct the interactome is 103/217 (47.5%) covered, up from 41.0%, and the read queue is now ZERO - no partner with two publications or two baits lacks an entry, so the instrument's own ranking criterion has stopped selecting anything. It was also persisting the list of partners that DO have entries while counting and discarding the 105 that do not, which is the exact defect cycle 57 fixed for the other list · Analysis
- The interactome tail is orderable after all, just not by evidence: 62 of the 96 unwritten partners are already DISCUSSED somewhere in this corpus and need only promoting to entries, while 34 have never been read at all. Two cycles looked for a priority order in evidence strength and found none, because the ordering that exists is over how much work is left, not over how good the evidence is · Analysis
- GSE299100 supplies the vehicle-versus-vehicle pair that neither GSE260742 nor GSE127507 could - two independent control hairpins, both DMSO, same date, uniformly processed to hg38_rmdup.tdf, for MEN1, MLL1 and input - in MV4-11, which Cellosaurus confirms carries KMT2A::AFF1 though it presents as monocytic rather than the infant B-ALL this project studies. It also holds MEN1 and MLL1 ChIP under five different menin inhibitors in that line, and the six control files total 1.87 GB · Analysis
- 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 · Gene
- The near-silent genome of infant KMT2A-r ALL — 1.3 non-silent mutations, and why that is bad news as well as good · Mechanism
- What is a fusion gene? · Explainer
- IGF2BP3 — an RNA-binding protein required for MLL-Af4 leukaemogenesis in mice that CRISPR barely touches in human lines · Gene
- Scott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug · Group
- Thomas Milne (MRC WIMM, Oxford) — MLL-AF4 target biology, enhancer architecture and PROM1/CD133 · Group
- Pablo Menendez & Clara Bueno (Josep Carreras Leukemia Research Institute, Barcelona) — cellular origin, fetal models and infant-specific drug resistance · Group
- The LEDGF hole, measured: every published LEDGF-removal experiment removes it BEFORE or AT transformation, and none treats an established leukaemia in an animal · Analysis
- The nuclear pore and NUP98 fusions — a fusion that takes a pore protein's disordered repeats off the pore and builds nuclear droplets with them · Mechanism
- The nucleolus — the one compartment with direct published images of a KMT2A fusion inside it · Mechanism
- The endogenous MLL-AF4 localisation experiment was unattributable, not negative: an anti-AF4 polyclonal in a t(4;11) cell images mostly wild-type AF4 · Mechanism
- FLT3-ITD signals from inside the cell, not from the surface - and whether it is the ER or the Golgi decides which pathway fires · Mechanism
- PAF1 is annotated as punctate everywhere in the nucleus EXCEPT the nucleolus - and a 2024 proximity map puts it in the nucleolus · Mechanism
- 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 · Mechanism
- H3K4me2 - the LSD1 substrate, and the only histone mark ever compared head-to-head between two KMT2A fusion partners in human cells · Mechanism
- Dataset: cBioPortal - open, easy, and containing exactly two KMT2A::AFF1 fusion records · Analysis
- AFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing · Protein
- 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 · Mechanism
- 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 · Explainer
- MRD by genomic breakpoint: the only assay in this disease that is fusion-specific by construction · Explainer
- MRD by fusion transcript: fast, standardised, partner-limited - and structurally blind to KMT2A* · Explainer
- MRD by Ig/TCR rearrangement: the standard in ALL, and the assay infant KMT2A-rearranged disease strains hardest · Explainer
- 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 · Explainer
- 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 · Explainer
- TNF — the only NF-kB-activating ligand with real KMT2A::AFF1 B-ALL evidence, and the evidence says the blasts are RESISTANT to it · Protein
- Bortezomib is called an NF-kB inhibitor, and in MLL leukaemia it does two different things in two lineages — neither of which is reliably NF-kB in the lymphoid one · Mechanism
- What is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule · Mechanism
- I-BFM childhood KMT2A-r AML (n=1,130): the 3-prime partner defines two risk groups that differ by 24 EFS points · Epidemiology
- Ponte-di-Legno non-infant KMT2A-r ALL (n=629): 5-year EFS spans 41.7% to 91.2% across partner-by-lineage cells · Epidemiology
- Infant BCP-ALL (n=175): KMT2A::AFF1 2-year EFS 36% versus 37% for every other partner (P=0.9) · Epidemiology
- 465 KMT2A-r B-ALL cases from 1 month to 89 years: partner predicts MRD clearance independently of age · Epidemiology
- The age confound: a partner arm and an age arm are nearly the same arm · Explainer
- AUGMENT-101: the partner composition of the trial that approved a menin inhibitor, with KMT2A::AFF1 at n=2 evaluable · Epidemiology
- KMT2A::USP2, inv(11)(q23.3q23.3) - the minor-BCR fusion that keeps the PHD fingers · Fusion
- The partner's deubiquitinase domain is what lets a PHD-retaining KMT2A fusion survive and transform · Hypothesis
- A six-month-old with a week of coughing: KMT2A::AFF1 pro-B ALL presenting with extreme hyperleukocytosis · Patient story
- Two clones, two antibodies: a four-month-old with refractory KMT2A::AFF1 mixed-phenotype leukaemia treated with blinatumomab and gemtuzumab together · Patient story
- Mixed phenotype acute leukaemia (MPAL) and acute leukaemia of ambiguous lineage · Disease
- Phase-2 dossier: the fusion junction - a negative feasibility finding, with the one surviving modality named · Target
- Is BENC even on in the disease this project is about? A module-resolved accessibility and deletion map in KMT2A::AFF1 B-lineage cells · Experiment
- AFF1's modern proximity neighbourhood is four RNA-binding proteins - NPM1, RBM15, SBDS, ZRANB2 - and it barely overlaps AFF4's · Analysis
- KMT2A sits in the 14-3-3 proximity neighbourhood, and the YWHAG link reproduces across two independent studies · Analysis
- 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 · Analysis
- The fusion begins at AFF1 residue 347 and the cyclin T1-binding sequence ends at 308, so KMT2A::AFF1 is the one AFF-family protein that cannot enter the reservoir · Mechanism
- 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 · Hypothesis
- The two t(4;11) products split AFF1 exactly at the P-TEFb-binding module, and the elongation half goes to the reciprocal · Mechanism
- PRMT5 - the type II arginine methyltransferase this graph has reached for sixteen times, whose mark on H3R2 RECRUITS WDR5 to chromatin · Protein
- 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 · Protein
- One demethylase family sits at both ends of this disease - KDM3B gates whether KMT2A rearranges, JMJD1C is what the resulting fusion needs to survive - and a single compound hits both, so its therapeutic index runs in opposite directions in the two cell populations it reaches · Hypothesis
- ATF4 / CREB2 (P18848) - the hub this graph inferred from its targets and never wrote, and its own transcript does not move under either menin inhibitor · Gene
- CHAC1 / BOTCH (Q9BUX1) - the largest single effect in the whole menin-inhibitor response (-5.11 log2) and a glutathione-degrading pro-apoptotic enzyme, named nowhere in this graph until now · Gene
- TRIB3 / TRB3 (Q96RU7) - a pseudokinase that is the ISR's own brake, falls 3.1 log2 under either inhibitor, and has a published physical link to the MLL complex in the wrong tissue · Gene
- 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 · Gene
- ATF5 / ATFX (Q9Y2D1) - the most reproducible repression in the earlier dataset, and the three probe values the graph quotes are SEM, not RS4;11 · Gene
- ATF3 (P18847) - the one cascade member the DOT1L inhibitor hits HARDER than the menin inhibitor, and a transcriptional REPRESSOR being counted as a stress output · Gene
- SESN2 / sestrin-2 (P58004) - the ISR's exit into mTORC1: a leucine sensor that falls 1.4 log2 under either inhibitor, and the one panel member with a real structural record · Gene
- STC2 / stanniocalcin-2 (O76061) - the second largest effect in the signature (-4.40 log2), a SECRETED glycoprotein, and its localisation rests on curator inference alone · Gene
- 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 · Gene
- IKZF3 / Aiolos (Q9UKT9) - the B-lymphoid transcription factor that goes UP under both inhibitors, regulates BCL2, and is a degradable drug target · Gene
- SGK1 / SGK (O00141) - a MENIN-SELECTIVE upregulated kinase, a druggable AGC family member, and the panel's worst platform disagreement · Gene
- EIF2AK4 / GCN2 (Q9P2K8) - the amino-acid-sensing eIF2alpha kinase: transcript flat, and NOTHING has ever been published about it in any KMT2A-rearranged system under either name · Gene
- One blot: phospho-eIF2alpha and ATF4 protein in RS4;11 under VTP-50469, with a dose-response and a DOT1L comparator arm · Experiment
- 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 · Analysis
- PHGDH (O43175) - the largest menin-SELECTIVE fall in the whole serine panel, and the least essential gene in it · Gene
- ALDH1L2 (Q3SY69) - the second-largest fall in the serine/one-carbon panel (-3.40), named nowhere in this graph, zero of 1,258 DepMap lines require it, and a tumour SUPPRESSOR where it has been studied · Gene
- SHMT2 (P34897) - the mitochondrial one-carbon step, and the paralogue that rises while it falls is why its loss may not matter · Gene
- 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 · Analysis
- A junction-specific monoclonal antibody against a paediatric leukaemia fusion oncoprotein exists: clone TEL 6F2, raised against a 12-mer spanning the ETV6::RUNX1 fusion site and used for genome-wide ChIP · Explainer
- The experiment this beat could not do: an epitope-tagged KMT2A::AFF1 ChIP with a Drosophila spike-in, in a human infant-derived B-lineage line, at three replicates and two menin-inhibitor exposures - the design that would turn a within-sample ranking into an absolute occupancy measurement · Experiment
- In human RS4;11 (KMT2A::AFF1), menin occupancy at its own top 0.1% of 2 kb bins falls 14.9x to 2.0x over the track median and its share of total coverage falls to 0.200 - reproducing Q117's murine FLAG-MLLAF9 figures (15.9x to 3.0x, ratio 0.179) to within 1.3-fold on all five statistics · Analysis
- In the human index fusion the menin inhibitor subtracts MENIN and leaves MLL1-N-reactive material in place at the same sites - so the drug's chromatin action is decoupling rather than eviction, and what this literature calls fusion eviction is a menin measurement · Hypothesis
- At the 692 RS4;11 bins where an MLL1 N-terminus and menin co-occupy, VTP-50469 takes menin to 0.20 and DOT1L to 0.20, drops H3K79me2 to 0.66, and leaves MLL1-N-reactive material at 0.83 - four factors, one drug, one chromatin, and a clean ordering · Analysis
- BAHCC1 - a BAH-domain H3K27me3 reader that an MLL fusion binds and upregulates in mouse, and the locus carrying the two largest MLL1-N-reactive rises under a menin inhibitor in human RS4;11 · Gene
- 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 · Gene
- RS4;11 - the human KMT2A::AFF1 index-fusion line - has a deposited H3K79me2 pair, a MENIN pair, an MLL1-N pair, a DOT1L pair and an input under the same menin inhibitor in GSE127507. Every track needed to run this beat's test on the index fusion exists. The download is 1.99 GB measured by HEAD request, and nobody has run it. · Analysis
- Download and bin GSE127507's nine RS4;11 tracks (1.99 GB), rebuild a human binner, and score the eviction gradient in the index fusion KMT2A::AFF1 - the one measurement that would move this finding from KMT2A::MLLT3 to the disease this graph is about · Experiment
- 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 · Non-coding
- 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 · Explainer
- 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 · Explainer
- Two groups invoke LIN28B to explain the SAME epidemiological fact in OPPOSITE directions - and neither claim is the one this graph has been repeating · Explainer
- CORRECTS A DISPATCH PREMISE: GSE149183's menin-versus-DOT1L-inhibitor head-to-head exists in MOLM13 (KMT2A::MLLT3) ONLY. RS4;11 - the index fusion - is in the series but carries H3K79me2 alone, with no VTP-50469 arm, no MEN1 ChIP and no DOT1L ChIP, and the two arms are on different genome builds · Analysis
- Differentiation syndrome is the one human pharmacodynamic readout KMT2A-rearranged leukaemia already shares with APL - and in APL it is a complication of a cure, while here it is a complication of a 30% response rate · Analogy
- A pocketless fusion already had its protein-protein-interface drug taken to phase I/II - and TK216 turned out to be a microtubule destabiliser, not an EWS::FLI1 antagonist. This is the closest thing the field has to a controlled failure of the interface hypothesis. · Analogy
- An H3K4me3-reading PHD finger fused to NUP98 makes a potent leukaemia oncoprotein; the H3K4me3-reading PHD finger of KMT2A is deleted from every KMT2A fusion and reinstating it abolishes transformation. Same module class, opposite sign - and the one NUP98 fusion that carries KMT2A's PHD cassette is the weakest member of its family. · Analogy
- A genuine small-molecule disruptor of an oncogenic oligomer DOES exist - 7.44 against the RUNX1::RUNX1T1 NHR2 tetramer - which corrects this graph's record; and its eighteen-year potency curve says the class is a chemistry problem, which is what this graph concluded for the wrong reason · Analogy
- 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. · Analogy
- CBFA2T3::GLIS2 supplies its own CAR-T antigen - FOLR1 came out of a list of fusion-specific genes in an isogenic human model. KMT2A-rearranged leukaemia is treated with a LINEAGE antigen it can abandon, or with one a drug has to create; nobody has built the fusion-specific surface list for KMT2A::AFF1. · Analogy
- 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. · Analogy
- The deposited RS4;11 H3K79me2 table in GSE149183 is two-thirds MOLM13: 38,580 of its 57,794 rows are byte-for-byte identical to the MOLM13 file, so the index fusion is measurable at only 19,214 TSS entries · Analysis
- On an absolute scale, H3K79me2 in the index fusion falls 52-fold (EPZ5676) to 91-fold (compound 10) by day 9 and NOT ONE of 17,341 measurable genes holds its signal - the first absolute-scale chromatin statement this project has been able to make about KMT2A::AFF1 · Analysis
- RS4;11 retains 2.5x more H3K79me2 than MOLM13 under EPZ5676 at every one of ten baseline deciles - and 0.71x under compound 10, with the sign reversing in deciles 5-10: the between-line difference survives the baseline confound and fails the drug replication, so it cannot be attributed to the fusion partner · Analysis
- Of every antigen this project names, only NG2, LAMP5 and CD123 are present on all three KMT2A::AFF1 cell lines - CD19 is at 0.2 nTPM in MV4-11 and CD33 at 2.3 in RS4;11 · Analysis
- REFUTED IN THE CYCLE IT WAS WRITTEN - the proposal that fusion-driven and normal-tissue-clean surface antigens are disjoint in KMT2A::AFF1 because of what the fusion's output programme is; an expression-matched permutation says it is the base rate · Hypothesis
- GSE159608 — 419 automated CUT&Tag libraries across 7 KMT2A-rearranged primary patient samples, 5 lines and a normal CD34+ donor, including KMT2A fusion occupancy, a menin-inhibitor arm in SEM, and three single-cell CUT&Tag libraries · Analysis
- In SEM, the infant-derived KMT2A::AFF1 line, VTP-50469 lowers H3K4me3 at menin-bound sites by 23% relative to H3K4me3-matched menin-free sites (95% CI 13-33%), while the DOT1L inhibitor EPZ-5676 changes it by 1% (CI -4 to +6%) · Analysis
- Spike-in-normalised menin CUT&RUN in a KMT2A::AFF1 degron line, with replicates and a PSIP1 arm · Experiment
- GSE252378 holds the only AFF1 CUT&RUN in primary KMT2A::AFF1 patient material - four libraries across two patients, three disease states and the SEM cell line, all hg38 · Analysis
- AFF1 occupancy does not distinguish fusion-occupied promoters from wild-type KMT2A promoters in primary infant KMT2A::AFF1 - reproduced at promoter resolution, and the corpus should stop reading a partner ChIP as a fusion readout · Analysis
- The taspase-1 N/C antibody control separates fusion-occupied from wild-type KMT2A promoters in every primary infant sample, and it is the C-terminal arm that does the work while being the less reproducible arm · Analysis
- The B-ALL and the AML of one infant share no more fusion-occupied promoters than two unrelated infants do - lineage, not patient identity, sets where KMT2A::AFF1 sits · Analysis
- Run a fusion-specific and a total-AFF1 readout side by side in the same KMT2A::AFF1 nuclei, and report the two target sets rather than one · Experiment
- The menin interface cannot be what decides where KMT2A::AFF1 sits: within one patient the fusion's target promoters were almost entirely replaced while the menin-binding motif was unchanged · Mechanism
- The menin that matters in an infant KMT2A-rearranged leukaemia is the menin on the fusion, and the N-minus-C antibody difference can measure it in any patient sample without a tag · Hypothesis
- Spike-in-normalised menin CUT&RUN with paired N- and C-terminal KMT2A antibodies in an infant KMT2A::AFF1 sample, on and off drug, in the same disease state · Experiment
- GSE252378 fragment BEDs: a complete KMT2A N-terminal / C-terminal antibody set in 27 patient samples across six fusion partners, deposited and until now unopened by this corpus · Analysis
- GSM8006584 names its antibody KMT2A-C1 in its title, its characteristics field and its own filename, and KMT2A-C2 in its description - so keying the antibody off the free-text description gives patient TB-92-0488 two C2 libraries and no C1 · Analysis
- The menin interface is identical in all 27 of these patients and the amount of chromatin their oncoproteins occupy differs by up to two orders of magnitude - so the interface can be a permission for binding but cannot be what sets how much binding happens · Mechanism
- IRX1 — Iroquois homeobox 1, the gene that names the HOXA-negative half of infant t(4;11) ALL · Gene
- SEM, the standard t(4;11) model line, has zero signal at IRX1 — every model of this disease is a model of one subgroup · Analysis
- GSE252378 holds eight KMT2A::AFF1 oncoprotein panels from two centres, not the three this corpus had used · Analysis
- 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 · Analysis
- The KMT2A::AFF1 oncoprotein-target promoter set is a fusion-level property, and patient identity adds nothing measurable on top of it · Hypothesis
- p279 and p318: one infant, two diseases, and an oncoprotein target map that does not carry over · Patient story
- IRX1 fusion occupancy is confined to KMT2A::AFF1: 0 of 18 samples across five other partners · Analysis
- TB920488, the other HOXA-negative IRX1-negative blast, has the highest GMP-over-B-lineage ratio of any B-lineage sample in the deposit - and it fails both the matched null and the N-over-C test · Analysis
- 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 · Analysis
- 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 · Analysis
- IRX2 - the IRX-cluster neighbour that is this disease's own prognostic gene, activated only in KMT2A::AFF1, and never written here until now · Gene
- The 'raw library promoter mean' that two cycles treated as library coverage tracks the in-promoter fragment FRACTION at Spearman +0.993 and true sequencing depth at only +0.292, and the oncoprotein share correlates with true depth at -0.255 · Analysis
- IRX2 is not fusion-occupied at promoter scale in GSE252378: 0 of 27 samples, against a null of 2.73 · Analysis
- The 17-promoter AFF1-only recurrent core is not more recurrence than a label permutation of the same matrix gives · Analysis
- The 332-promoter AFF1-only set is BELOW the count a random eight-sample arm produces (null 425) · Analysis
- AFF1's promoter window is 92.5% AFF1-AS1's - worse than IRX2's 89.2% - and the project's promoter table has no row for the neighbour at all · Analysis
- 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 · Analysis
- In the deposit paper's own target-gene table, the AFF1-exclusive class is 64 genes against a permutation null of 2.3, and it survives call-rate matching, institution stratification, B-lineage restriction and patient collapse · Analysis
- At gene-body scale the AFF1-exclusive recurrent class is 6 against an exact institution-stratified null of 0.86 - but the singleton class is 63 against 74, so recurrence carries the signal and exclusivity alone does not · Analysis
- AFF1-AS1 - the antisense RNA 151 bp from the index fusion partner's TSS, which Ensembl does not recognise and this project's promoter table cannot see · Gene
- AFF1's own promoter window is occupied in 20 of 27 samples - top 4% of the whole table - and the call cannot be attributed to AFF1 · Analysis
- The prey-only interactome is 36.3% written, not 0% - the census, by identity, of all 212 human prey-only partners of the six core proteins · Analysis
- 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 · Analysis
- Every MS-evidenced KMT2A modification site, flagged retained or lost against the breakpoint - and the retained portion is NOT enriched for acetylation once you use the right null · Analysis
- Ranked against four fusion families, the KMT2A acetylation site is the only candidate with no evidence on the fusion at all - and the strongest argument for it is one nobody has made · Analysis
- AKAP95 reaches this disease by two separate routes - through WRAD/DPY30 and through the retained KMT2A fragment - and only the second one survives the fusion · Explainer
- The lymphoid-restricted DAXX dependency survives three nulls and two comparator restrictions - and ATRX, MEN1 and DOT1L do not survive the same test in the same lines · Analysis
- Nobody has ever looked at whether a KMT2A fusion is at PML nuclear bodies - a counted zero, with the one biochemical hint pointing yes · Mechanism
- FLT3 in ZNF384-rearranged leukaemia - the fusion builds its own enhancer 25 kb upstream, and gilteritinib works in xenografts · Target
- "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 · Analysis
- 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 · Analysis
- LEF1 — the Wnt/β-catenin DNA-binding factor of the T-lineage, named as an MLL-AF4-specific interactor in a T-ALL cell line and with essentially no B-lineage or KMT2A literature · Gene
- KMT2A::AFF1 has no measured fusion-specific interactome: the one dataset that appears to supply one is a rank-selected tail in the wrong lineage, and the question is open rather than answered badly · Hypothesis
- Every WRAD subunit, DOT1L, ENL, AF9 and LEDGF carries a cited histone-mark finding and none carries an epigenetics field - 12 of the 32 index-fusion core proteins are pure notation gaps, 9 are covered, and the 11 with nothing are all on the negative-regulatory side of elongation · Analysis
- 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 · Analysis
- What the paralogues' disease biology says about AFF1: the AFF family shares one SIAH degron — and the index fusion DISCARDS it, because the whole degron lies in the AFF1 leader that the junction at residue 347 throws away · Mechanism
- No fusion oncoprotein in any family has a published replication-protein-A measurement: 23 queries across five fusion families and four spelling variants each, every querytranslation read back, zero records - so the PI's analogy dimension for RPA has no comparator at all, and the index fusion's single locus-level result is the entire field · Analysis
- 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 · Analysis
- 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 · Protein
- No experiment has ever ASKED whether MTA2, MBD3, GATAD2A or SIN3A binds a KMT2A fusion - four of them were nonetheless in the lysate of a seven-fusion pulldown, and the class of that absence is measured-not-reported, not never-measured · Analysis
- 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 · Hypothesis
- 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 · Hypothesis
- SPP1 (osteopontin) - the endosteal matrix protein whose knockdown prolongs survival in MLL-AF9 mice, and the one KMT2A::AFF1-specific paper about it cannot be read · Gene
- Niche biology HAS been measured in KMT2A-rearranged disease - but in the index fusion itself there is essentially one marrow-niche molecular experiment, from 2011 · Analysis
- 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 · Gene
- 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 · Gene
- LMO2 (rhombotin-2) - a bridging LIM-only protein, higher in pro-B and MLL-rearranged B-ALL, anti-selective in KMT2A-rearranged lines, and a physical partner of the KDM5A module that NUP98::KDM5A retains · Gene
- 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 · Gene
- AFF1 reaches P-TEFb only through AFF4, and the index fusion's elongation phenotype is therefore a claim about AFF4 availability · Hypothesis
- IntAct curates SEVEN MLL fusion proteins as first-class interactors - ENL, AFF4, AF9, GAS7, ELL, AF6 and CALM - and not the index one · Analysis
- 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) · Analysis
- 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 · Analysis
- Ten affinity measurements for this contact and not one uses a fusion protein, full-length KMT2A or a nucleosome · Analysis
- The pivotal menin-inhibitor paper reports that the drug does NOT globally displace MLL1 or the fusion from chromatin - menin goes, the fusion largely stays · Mechanism
- Bounded absence: no published study has tested whether a KMT2A fusion GAINS chromatin sites under a menin inhibitor - and the same pipelines found gains for two other proteins when they looked · Analysis
- Bounded absence: every chromatin measurement under a menin inhibitor is in an adult-derived line, and none is in an infant KMT2A::AFF1 model · Analysis
- Hypothesis: the menin inhibitor's effect is inactivation in place, not eviction - the fusion keeps most of its sites and loses its output · Hypothesis
- 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 · Gene
- 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 · Gene
- 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 · 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Protein
- MED19 - the Mediator subunit curated against an engineered MLL-AFF4 fusion protein, and the one REST uses to deliver G9a · Protein
- BUD13 - a RES-complex splicing factor 1.66 Mb from KMT2A on 11q23.3, whose one chromatin paper puts it in the soluble fraction · Protein
- The infant breakpoint mutilates the reciprocal protein's first PHD finger - so 'the reciprocal product' is at least two different proteins · Explainer
- Competing model 3: reciprocal status is a proxy for where the break fell, and the thing that changed is the DIRECT product · Hypothesis
- A tested negative: neither fusion product alters DNA double-strand break repair · Explainer
- The MLL3/4-UTX switch fails to throw — menin inhibition kills by turning something ON, and cells that cannot turn it on survive · Resistance
- Three addresses, one output: what SET::NUP214 actually does to the menin-interface hypothesis, and why it is a weaker test than CALM-AF10 · Explainer
- The soluble-nucleoplasm versus chromatin-bound axis - the one localisation readout that keeps a size dimension, and nobody has run it on a KMT2A fusion · Mechanism
- The clustered PHD fingers (KMT2A aa 1416-1640) are a chromatin-targeting module and the canonical t(4;11) junction removes them by ten residues · Mechanism
- MLL was reported at regions attached to the nuclear envelope in 2000, which is indirect evidence at the lamina that this graph currently records as absent · Mechanism
- Hypothesis: what the KMT2A half loses is control of its own abundance, not control of its activity · Hypothesis
- TASP1 (taspase1) - the protease that cuts KMT2A, and the timer the fusion escapes · Protein
- AFF1 as the subtraction control: the refutation is WITHDRAWN - the degron is lost, not retained · Mechanism
- Experiment: CRISPR knockout of CLEC12A in KMT2A-rearranged models, with and without a cooperating RAS lesion · Experiment
- FUT4 - the myeloid alpha-1,3-fucosyltransferase, a hub gene of the KMT2A-rearranged expression module, and the gene HGNC once officially called CD15 · Gene
- SS18 - a SWI/SNF subunit that is itself a fusion partner in another cancer, and a lineage-independent dependency in KMT2A-rearranged lines · Protein
- 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 · Mechanism
- In human KMT2A::AFF1 MV4;11 (monocytic, not B-lineage), the vehicle-versus-vehicle noise floor is 9.4% at the top 0.1% of menin/MLL1 sites and 0.1-2.6% in every other stratum - so cycle 102's borrowed 4-10% band is about right AT THE PEAKS and four to five times too generous everywhere else, and it was applied everywhere · Analysis
- The missing reagent is a spike-in, not a better statistic: a spike-in-normalised H3K4me3, H3K79me2 and H3K27me3 ChIP-seq at 72 h of a clinical menin inhibitor in a KMT2A-rearranged human line, which is the only design that can tell a genuine genome-wide mark redistribution from the compositional shadow of a peak-localised change · Experiment
- Does menin inhibition have any MHC class II headroom to work with in B-precursor infant ALL? A flow cytometry experiment on samples that already exist · Experiment
- A caveat that weakened the index fusion, wrongly: the MLL-AF4 spreading deposition is 30 SEM samples plus six other lines, all human · Analysis
- The panobinostat H2Bub result is SEM and KOPN8 against a REH comparator: three human lines, two KMT2A partners, one non-KMT2A control · Analysis
- The unnamed KMT2A-rearranged B-ALL line is SEM, and the deposition says KMT2A::AFF1 in a genotype field · Analysis
- 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 · Analysis
- Bounded failure: the one unresolved source that is actually about the index fusion · Analysis
- 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 · Explainer
- Cord blood does transform — when the translocation is engineered rather than expressed · Explainer
- WDR5: an established wild-type KMT2A contact, and no fusion contact ever measured · Explainer
- RBBP5: the thinnest fusion literature of the four subunits, and one chromatin datum · Explainer
- ASH2L: the only WRAD subunit ever perturbed in a KMT2A::AFF1 cell, once, weakly · Explainer
- DPY30: the founding negative does not cover it, and it has no KMT2A contact to lose · Explainer
- Forty-five percent of t(4;11) patients express a KMT2A fusion transcript that keeps the whole WRAD interface · Explainer
- An anti-MLL-C antibody in a t(4;11) cell is looking at two proteins at once · Explainer
tests · 49
- Catalytic-dead versus degrader: a four-arm test that resolves the HDAC7 direction conflict and supplies the pharmacodynamic marker this drug class has never had · Experiment
- Settle the monocytic confound isogenically: degrade the fusion, read haem-gene dependency before lineage has time to move · Experiment
- Cell type or the fusion? MV4-11 LOOSENS the confound the graph's own lineage split was built on - but its founding paper calls it biphenotypic · Analysis
- Put the same fusion in two cell types and degrade it, rather than cutting the gene · Experiment
- In-silico digest of 81 modelled KMT2A fusion junctions: the peptide that would prove the fusion protein exists · Analysis
- Targeted PRM for the KMT2A::AFF1 junction peptide - the experiment that makes every other attribution claim testable · Experiment
- Attribution audit 1 of 5 - who co-purifies with KMT2A::AFF1: the inventory does not survive, the individual partner blots mostly do · Analysis
- Attribution audit 2 of 5 - post-translational modifications on KMT2A::AFF1: nothing survives at peptide level, and the one strong PTM result is explicitly about the wild-type protein · Analysis
- Attribution audit 3 of 5 - where KMT2A::AFF1 sits in the nucleus: the endogenous image does not survive, the overexpression images do and say something different · Analysis
- Attribution audit 4 of 5 - the half-life and turnover of KMT2A::AFF1: this class SURVIVES, and it is the only endogenous fusion-attributable protein measurement this beat found · Analysis
- 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 · Analysis
- Junction RT-PCR is the one routine assay in this disease that IS fusion-specific - and it is structurally blind to KMT2A* · Explainer
- Knock a tag-plus-degron cassette into the endogenous KMT2A::AFF1 allele in SEM - one construct that makes five claim classes attributable · Experiment
- Does KMT2A::AFF1 bind the histone chaperone SET/TAF-I beta, and does that contact overlap the menin-binding motifs? A co-IP and a peptide competition · Experiment
- Separate positioning from catalysis: an ASH2L mutant that keeps RBBP5 and loses DPY30 · Experiment
- First systematic enumeration of the KMT2A fusion interactome, and the diff against this graph · Analysis
- Proximity-labelling map of KMT2A::AFF1 — the experiment nobody has run in twenty years of interactome work · Experiment
- Measure the pausing index at KMT2A::AFF1 target genes — the one number the whole pausing argument turns on, and it has never been reported · Experiment
- The decisive experiment: acute degron removal of IGF2BP3, IGF2BP2 and both, read on self-renewal and xenograft initiation rather than bulk dropout · Experiment
- Step 5: molecular confirmation and naming the partner · Explainer
- Correcting the fusion with genome editing: verdict NOT FEASIBLE for infant leukaemia, though intron-targeted disruption is a real published strategy · Target
- Step 4: the split-signal FISH nucleus - one fusion, one green, one red · Explainer
- Step 3: the G-banded karyotype and t(4;11)(q21;q23) · Explainer
- Experiment: build the missing KMT2A::AFF1 degron and titrate it — what fractional occupancy does the program actually need? · Experiment
- Combine an IKK inhibitor with a clinical menin inhibitor in a KMT2A::AFF1 B-ALL line, and read out fusion OCCUPANCY rather than viability · Experiment
- One immunoprecipitation that decides whether 14-3-3 touches KMT2A at all · Experiment
- 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 · Experiment
- The one experiment that would close the SUV39H1 arm of this graph's H3K9 argument: CST #8729S CUT&RUN in a CD34+ progenitor and in SEM or RS4;11, with an IgG arm and a SUV39H1-degron arm that neither existing deposit has - because after this cycle the enzyme has been measured in exactly two human cell types and neither is a blood cell · Experiment
- Raise a KMT2A::AFF1 junction-specific monoclonal by the published TEL 6F2 protocol - rat immunisation with a junction peptide, ELISA and western screen, then a ChIP test against the wild-type-parent controls that the ETV6::RUNX1 campaign never ran · Experiment
- Tag the endogenous KMT2A::AFF1 allele in RS4;11 and ChIP the tag with and without VTP-50469 alongside MENIN and MLL1-N in the same chromatin - the one experiment that converts every occupancy claim in this literature from a reagent statement into a fusion statement · Experiment
- 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 · Experiment
- PROPOSED: swap the partner, hold everything else - KMT2A::MLLT3 versus KMT2A::AFF1 in LIN28B-null human fetal liver CD34+ cells · Experiment
- The one experiment that would close this beat: MEN1 and DOT1L ChIP in RS4;11 (KMT2A::AFF1) under DMSO, a menin inhibitor and a target-engaging DOT1L inhibitor, with Drosophila spike-in and two replicates per arm - about 24 libraries, and the depositing lab already runs every component of it · Experiment
- Six to twenty-four libraries in RS4;11: two DOT1L inhibitors titrated to equal spike-in-measured global H3K79me2 loss, three replicates per arm, plus the no-primary control that no public deposit contains - the smallest experiment that would convert four moderate entries in this beat into testable ones · Experiment
- A surfaceome-first screen for KMT2A::AFF1: 2,404 surface proteins, 169 expressed in the fusion's own cell lines, 15 fusion-enriched, 3 clean in normal tissue - and the two sets do not intersect · Analysis
- Cell-surface capture proteomics on an isogenic human KMT2A::AFF1 model against its matched normal progenitor - the experiment an mRNA screen cannot replace · Experiment
- IRX1 carries the KMT2A::AFF1 oncoprotein in exactly the patients where HOXA does not — seven patients, GSE252378 · Analysis
- Four hours of MS67 in MV4;11, two KMT2A antibodies: the cheapest test of whether WRAD reaches the fusion or only wild-type KMT2A · Experiment
- 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 · Experiment
- 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 · Analysis
- Experiment: spike-in-calibrated, fusion-attributable occupancy of KMT2A::AFF1 in the first 24 hours of menin inhibition, scored for gains as well as losses · Experiment
- 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 · Experiment
- Experiment: five-fraction subcellular blot of a t(4;11) line, with a menin-inhibitor arm - converting thirty years of unattributable images into attributable numbers using only existing antibodies · Experiment
- Redesign: the proximity-labelling map of KMT2A::AFF1 cannot be controlled with the wild-type allele - it has to be controlled with time · Experiment
- Experiment: titrate wild-type KMT2A up and down in one leukemia cell and watch what happens to the fusion's grip on chromatin · Experiment
- Experiment: put four residues back - the minimal add-back control the PHD3 result has never had · Experiment
- Separate ncBAF from canonical BAF in KMT2A-rearranged cells: paired degron, paralogue-pair CRISPR, and complex-resolved CUT&RUN · Experiment
- One experiment that decides whether KDM4C is a target or the KDM4 family is: paralogue rescue of SD70 sensitivity in SEM · Experiment
- Settle the WRAD question: tagged co-IP plus degron-timed proximity across three fusion classes · Experiment
binds · 47
- RTF1 — the PAF1C subunit the graph was missing, on a complex that does bind the retained KMT2A fragment · Protein
- MLLT1 / ENL — the reader that beat its own paralogue, with a degrader already in hand · Protein
- MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is · Protein
- CBX8 — the one place in this interactome where two good papers flatly disagree, and DepMap takes a side · Protein
- KAT7 / HBO1 — an enzyme, a leukaemia-stem-cell dependency, and an inhibitor already in a crystal · Protein
- MEN1 / menin — the adaptor the fusion cannot work without · Protein
- PSIP1 / LEDGF p75 — the tether with the best therapeutic index in the whole interactome · Protein
- DOT1L — the target where excellent chemistry met an indirect interaction · Protein
- 14-3-3 theta binds AF4 at Ser588 and rides into the MLL-AF4 complex - the phospho-gated contact the fusion really does carry · Interface
- IRX1 binds the MLL-AF4 complex non-competitively — menin, LEDGF and DOT1L are all unchanged · Mechanism
- SETD2 (Q9BYW2) - the H3K36 trimethyltransferase that binds all seven MLL fusions, and the only one of them with a published KMT2A::AFF1 dependency test · Gene
- CHD4 (Q14839) - the NuRD ATPase, a pan-MLL-fusion co-purifier, and the gene whose disruption drives lineage switching in KMT2A::AFF1 relapse · Gene
- CSNK2B / CK2beta (P67870) - the regulatory subunit of casein kinase 2, in the pan-MLL-fusion core, with no CSNK2B-and-KMT2A literature at all · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- SPEN / SHARP / MINT (Q96T58) - the RNA-binding corepressor that silences the X chromosome, in the pan-MLL-fusion core · Gene
- JADE3 / PHF16 (Q92613) - the HBO1-complex scaffold with the strongest pan-fusion evidence in this beat, and an independent published contact with MLL · Gene
- 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 · Gene
- MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7 · Gene
- TPR / Megator (P12270) - the nuclear-basket nucleoporin that builds heterochromatin exclusion zones, in the pan-MLL-fusion core · Gene
- NUDT21 / CFIm25 (O43809) - the CFIm subunit that picks poly(A) sites, in the pan-MLL-fusion core, and a paraspeckle protein · Gene
- 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 · Gene
- 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 · Gene
- NUP50 / Npap60 (Q9UKX7) - a MOBILE nuclear-basket nucleoporin in the pan-MLL-fusion core, and the evidence says basket, not nuclear envelope · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- WBP11 (Q9Y2W2) - a splicing activator in the pan-MLL-fusion core, isolated from its own partners, and a human haploinsufficiency gene · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- EIF4G1 (Q04637) - a translation-initiation scaffold in the pan-MLL-fusion core, alone, with no other eIF4F subunit anywhere in the 960 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- 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 · Gene
- KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR · Protein
analogous to · 33
- CBFB — domain architecture and residue coordinates · Protein
- PICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A · Fusion
- 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 · Gene
- NUP98::KMT2A, inv(11)(p15q23) — the NUP98 fusion that contains KMT2A and is menin-inhibitor RESISTANT · Fusion
- LPP (lipoma-preferred partner) - a KMT2A fusion partner in acute monoblastic leukaemia whose day job is adhesion mechanotransduction, and which is barely expressed in leukocytes · Gene
- Why PML::RARA became curable — and what KMT2A::AFF1 does not share with it · Explainer
- PML nuclear bodies and PML::RARA — the best-worked case of a fusion destroying a nuclear compartment, and what it actually predicts for KMT2A · Mechanism
- BRD9::NUTM1, t(5;15)(p15.33;q14) - one fusion is enough to make infant B-ALL in a mouse, and it is the one that behaves best in a child · Fusion
- ACIN1::NUTM1 - the commonest NUTM1 fusion in infants, cryptic to cytogenetics, and the only one with a human cell line · Fusion
- ZMYND11 (BS69) - an H3.3K36me3 reader that restrains elongation, is itself the 5' partner of a chromatin-hijacking AML fusion driving HOXA/MEIS1/MYB, and whose promoter is the third-strongest MLL1-N bin in RS4;11 · Gene
- 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 · Fusion
- 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 · Fusion
- PML::RARA, t(15;17)(q24;q21) · Fusion
- EWSR1::FLI1 (EWS-FLI1), t(11;22)(q24;q12) · Fusion
- NUP98::KDM5A (NUP98-JARID1A), t(11;12)(p15;p13) · Fusion
- RUNX1::RUNX1T1 (AML1-ETO), t(8;21)(q22;q22) · Fusion
- NPM1::ALK (NPM-ALK), t(2;5)(p23;q35) · Fusion
- CBFA2T3::GLIS2, inv(16)(p13.3q24.3) · Fusion
- ETO2::GLIS2 rewires chromatin in stages and hijacks the osteogenic homeobox factor DLX3 as its first required step — a genome-edited human iPSC model that resolves leukaemia initiation into an ordered sequence · Mechanism
- 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 · Analysis
- EP300::ZNF384 - the commonest ZNF384 fusion, and it throws away the acetyltransferase · Fusion
- ZNF384::TEX41 - the case that breaks the family's architecture: ZNF384 is the 5' partner, the 3' partner is a lncRNA, and the fusion is out of frame · Fusion
- KMT2A::ELL (MLL-ELL), t(11;19)(q23;p13.1) · Fusion
- BCR::ABL1 (Philadelphia chromosome), t(9;22)(q34;q11) · Fusion
- ETV6::RUNX1 (TEL-AML1), t(12;21)(p13;q22) · Fusion
- DUX4::IGH (IGH-DUX4), t(4;14)/ins(14;4) — D4Z4 repeat insertion into the IGH locus · Fusion
- KMT2A::MAML2, inv(11)(q21q23) - a therapy-related fusion that also causes a solid tumour · Fusion
- 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 · Fusion
- YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away · Fusion
- VIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon · Fusion
- In leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that. · Explainer
- Every published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions · Analysis
- LDB1::KMT2A - the clearest statement in this literature that a sarcoma fusion keeps KMT2A exons 4 to 36 and discards exons 1 to 3 · Fusion
regulates · 25
- 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 · Gene
- 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 · Gene
- H2BK120ub (H2Bub1) — the ubiquitin tag on histone H2B that licenses H3K79 methylation, and the mark this graph was missing · Mechanism
- CDK6 - the kinase the KMT2A-r rationale actually rests on, and the pan-essentiality flag and the selectivity are both true · Gene
- CSPG4 / NG2 - the flow-cytometry surrogate for a broken KMT2A, and a direct target gene of the fusion that makes it · Gene
- 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 · Gene
- BCL2 — the one co-dependency in this beat that already has an approved drug pointed at it · Protein
- HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it · Protein
- RUNX1 — activated by KMT2A::AFF1 and then bound by the reciprocal fusion, in the one published two-oncoprotein circuit in t(4;11) · Protein
- KHDRBS1 (Sam68) — an RNA-binding protein that holds the MLL-AF4 message DOWN, a class no dropout screen can find · Gene
- RNA-binding proteins set how much KMT2A::AFF1 protein a cell makes from its own fusion transcript · Mechanism
- 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 · Gene
- miR-9 — the most MLL-specific microRNA in AML, encoded at three separate loci nobody has disambiguated · Non-coding
- IGF2BP3 — an RNA-binding protein required for MLL-Af4 leukaemogenesis in mice that CRISPR barely touches in human lines · Gene
- 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 · Mechanism
- CSNK2A1 (casein kinase 2 alpha) - the one kinase that turns up three separate times in KMT2A biology · Gene
- 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 · Gene
- 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 · Gene
- NG2/CSPG4 is the one antigen in the whole surfaceome that KMT2A::AFF1 itself drives - and it is a pericyte and vascular protein, at 124.5 nTPM in normal blood vessel and 246 TPM in tibial artery · Target
- LAMP5 (BAD-LAMP) - a direct MLL-fusion target gene, a proposed immunotherapy antigen, and a brain protein · Gene
- EPHA7 - ephrin type-A receptor 7, a published direct promoter target of the ALL1/AF4 (KMT2A::AFF1) fusion protein · Gene
- The partner, not the site, is what could make a retained KMT2A modification fusion-specific - the AML1-ETO mechanism asked of KMT2A::AFF1 · Hypothesis
- HOXA7 - the one HOXA paralogue besides HOXA9 with a published loss-of-function requirement for MLL-fusion transformation, and the requirement was shown in vitro only · Gene
- Re-founding the address argument: the CXXC domain cannot specify a location at any affinity, and a tighter one would be worse · Mechanism
- CCND3 (cyclin D3) — the scan's rank-4 hit, and the only one of the four with a drug class already in children · Protein
part of · 24
- AFF1 / AF4 — domain architecture and residue coordinates · Protein
- The other half of the break: what is actually known about the AFF1 breakpoint region, and the negative-control gene nobody cites · Mechanism
- 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 · Interface
- MBM2, the second menin-binding motif of KMT2A (residues 23-40): 26-fold weaker than MBM1, never separately co-crystallised, and the only part of the menin grip a drug is not aimed at · Interface
- AFF1-AFF4 heterodimerisation through the C-terminal homology domain: the one SEC interface KMT2A::AFF1 certainly keeps, defined by a 2.2 A structure of the wrong subunit · Interface
- 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 · Interface
- KMT2A 747-755 on HLA-B*07:02: a phosphoneoantigen from the half of KMT2A every fusion keeps, with seven crystal structures and a cognate TCR · Interface
- KMT2A minor breakpoint cluster region (BCR2): intron 20 - exon 24 · Breakpoint
- KMT2A / MLL1 — the gene that breaks · Protein
- AFF1 / AF4 — the 3' half of the fusion, and a target with almost no structural footing · Protein
- The fusion junction itself as a small-molecule target: a candid verdict · Target
- AK_7_3, a KMT2A::AFF1-derived fusion circRNA that holds down mitochondrial respiration and ROS in t(4;11) B-ALL - the only mitochondrial mechanism in this beat measured in the index fusion · Mechanism
- 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 · Mechanism
- Partner import: when a mechanism measured in one fusion is asserted about another · Explainer
- AFF1 AF4_int motif to AF9/ENL AHD: the index fusion's only documented elongation interface, and it competes with DOT1L · Interface
- 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 · Hypothesis
- Repeat the H3K79 partition in a human KMT2A::AFF1 line: menin inhibition and MLLT10 knockout, side by side with a KMT2A::MLLT3 line · Experiment
- What could refute the menin-interface bet, restated after the provenance audit: three tests, none of which is about menin binding · Hypothesis
- Bite-back: a target nominated from an imported mechanism inherits a fusion the index disease does not have · Risk
- SEC — the AFF1/AFF4-scaffolded super elongation complex, the particle KMT2A::AFF1 is a permanent subunit of · Protein
- The MT/BCB domain, Q03164 1147-1244: the CXXC fold plus a 41-residue basic tail nobody has measured on its own · Interface
- Lost from the KMT2A half: the four-residue HCF-binding motif (DHNY, aa 1799-1802) · Mechanism
- Lost from the KMT2A half: the WIN motif and the whole WRAD interface (aa 3762-3767, Arg3765) · Mechanism
- AFF1 as the subtraction control: the refutation is WITHDRAWN - the degron is lost, not retained · Mechanism
depends on · 17
- ATR - the replication-stress kinase with the best preclinical case in this disease and the best published reason not to inhibit it · Gene
- WEE1 - the one checkpoint target with a KMT2A::AFF1-specific result, and the paper that also found the escape route · Gene
- Hypothesis: KMT2A::AFF1 is continuously required, not a hit-and-run initiator whose job is done once the epigenome is set · Hypothesis
- FLT3 / CD135 — the strongest non-tether co-dependency, and a target the field may have written off on a badly executed trial · Protein
- PTBP1 — the strongest RNA-layer dependency in KMT2A-rearranged lines, found by a domain-focused screen and missed by this beat's own gene panel · Gene
- TERT — telomerase, switched on by the index fusion through HOXA7 · Gene
- ITGA4 (VLA-4) and NG2 — the niche-adhesion axis of KMT2A-rearranged B-ALL, and the one approved drug that hits it · Mechanism
- ELOVL1 - the fatty-acid elongase that infant MLL-AF4 ALL retains from its fetal origin, and the lipid enzyme on the opposite side of the divide from ACSL4 · Protein
- Phase-2 dossier: the LEDGF/PSIP1 IBD - the best therapeutic index in the interactome, a solved structure, two hotspot residues, and three compounds in the world · Target
- 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 · Gene
- LIN28B - a one-row BioID prey of KMT2A that a 2026 Blood paper shows is REQUIRED for KMT2A::AFF1 to transform human fetal cells · Gene
- IRX1 is a second address for the KMT2A::AFF1 oncoprotein, not merely the gene that turns HOXA off · Hypothesis
- 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 · Gene
- ARID4B / SAP180 (Q4LE39) - the Sin3A-complex subunit that shares SIN3A's HDAC1-binding region, is in the MLL-fusion interactome, and is the second of only two epigenetic vulnerabilities a CRISPR screen found in KMT2A-rearranged ALL · Gene
- SETD2 (Q9BYW2) - the H3K36 trimethyltransferase that binds all seven MLL fusions, and the only one of them with a published KMT2A::AFF1 dependency test · Gene
- The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential · Mechanism
- BOD1L (BOD1L1) — the top SETD1A co-dependency, and the only candidate in this cycle tested by CRISPR tiling in a KMT2A::AFF1 line · Protein
causes · 12
- TOP2A - the proliferation isoform, the one the drugs are actually measured against, and the only one with a germline association in this disease · Gene
- The non-synchronisable state: five KMT2A-rearranged lines refuse mimosine, double thymidine and nocodazole, and the fusion protein does not fluctuate through the cycle · Cell state
- The innate-immune-rewired state — LAMP-5 is a direct fusion target that routes signalling away from interferon and toward NF-kB, and the cell depends on that routing · Cell state
- The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia · Cell state
- The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell · Cell state
- The pro-B arrest state — what a KMT2A::AFF1 blast is actually doing while it sits there · Cell state
- The primed chromatin state — what is actually established, and why the word 'bivalent' should be used carefully here · Cell state
- Where KMT2A-rearranged leukemia physically sits — marrow niche, CNS, blood, liver/spleen and skin · Mechanism
- The CD24-positive pre-leukaemic state — what the index fusion makes before it makes leukaemia · Cell state
- Infant acute lymphoblastic leukaemia (ALL diagnosed under 1 year of age) · Disease
- Topoisomerase II cleavage and TOP2 poisons as a source of KMT2A breaks · Mechanism
- Which repair pathway glues the fusion together: classical NHEJ vs alternative end joining · Mechanism
refutes · 11
- The reciprocal fusion (AFF1::KMT2A and friends): a second oncoprotein that opens chromatin for the first · Mechanism
- RBBP5 — a WRAD subunit that binds the one part of KMT2A every fusion throws away · Protein
- ASH2L — the WRAD subunit that has DPY30's essentiality profile and none of its co-dependency signal · Protein
- KDM6A / UTX — a commonly asserted KMT2A partner that belongs to a different complex and points the opposite way · Protein
- RAG off-target activity: the dominant mutator in ETV6::RUNX1 ALL, and probably not the cause of KMT2A fusions · Mechanism
- Open ground: the questions in this graph that nobody in the landscape appears to be working on · Hypothesis
- The CRISPR-ChIP H3K79 partition is a mouse MLL-AF9 result: resolved from GEO after the full text proved unreachable · Analysis
- HOXB4, the one direct IRX1 target with ChIP evidence, carries no oncoprotein in any of seven infant patients · Analysis
- The fusion-biased peak at the AFF1 locus fires in 23 of 27 samples across all six partners, so it is not the fusion visiting its own partner · Analysis
- UBTF tandem duplications INVENT an export signal, and that invented signal is what puts the protein on chromatin - the cleanest proof the XPO1 address is real · Mechanism
- Chromatin-bound XPO1 as a shared, druggable address for HOXA-driven leukaemia - and the objection that it may be a general chromatin cofactor rather than an address at all · Hypothesis
supports · 11
- Retained fetal programme — the infant-versus-adult stem cell difference, and the reason KMT2A::AFF1 needs no second mutation · Cell state
- Subclonal cooperating lesions lost at relapse - what was actually measured, and why 'lost' is the wrong word · Mechanism
- The trans-histone crosstalk H2Bub → DOT1L → H3K79me: modulatory for me1, effectively required for me2/me3 · Mechanism
- KMT2A / MLL1 — the gene that breaks · Protein
- Step 3: the G-banded karyotype and t(4;11)(q21;q23) · Explainer
- The index fusion DISCARDS the SIAH degron: the junction is at AFF1 residue 347, the degron is at human 282-304, and three entries had it the other way because they measured a murine motif against an exon-numbering junction · Analysis
- RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin · Protein
- 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 · Analysis
- The imports that were never necessary: H3K79 methylation in KMT2A::AFF1 has its own literature, and this graph barely cites it · Analysis
- In an unsupervised 5 kb correlation of 41 SEM libraries, both KMT2A N-terminal AutoCUT&RUN libraries have menin as their single nearest neighbour - the menin-interface hypothesis appearing as the top-level structure of an analysis that was not looking for it · Analysis
- The menin interface is a requirement of 5'-KMT2A fusions in haematopoiesis, not of KMT2A rearrangement as such - and a solid tumour has been quietly proving it for six years · Hypothesis
co-occurs with · 9
- KRAS - the commonest co-mutation in a disease that has almost none, and it is usually in a minority of the cells · Gene
- IGF2BP2 — the paralogue co-over-expressed with IGF2BP3 in MLL/AF4 B-ALL, and the one with an inhibitor in another leukaemia · Gene
- KRAS as a co-mutation in KMT2A-r leukemia — the single most frequently co-mutated gene, and it still cannot start the disease · Gene
- NRAS as a co-mutation in KMT2A-r leukemia — the one co-lesion that is specifically enriched in t(4;11) · Gene
- FLT3 in KMT2A-r leukemia — near-universal overexpression, but activating mutation in only ~3% of infants · Gene
- Kinase/PI3K/RAS pathway activation — the only common co-lesion class in KMT2A-r leukemia, and it is mostly subclonal · Pathway
- KMT2A::SEPTIN11 (MLL-SEPT11) — the fusion that cytogenetically impersonates t(4;11) · Fusion
- AFF1::KMT2A (AF4-MLL), the der(4) product: what it is made of, residue by residue · Protein
- Put both fusion proteins in the same cell and you get something neither produces alone · Mechanism
treated by · 7
- 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 · Drug
- I3IN-002 — the first small-molecule IGF2BP3 inhibitor with in vivo activity in an MLL-Af4 model · Drug
- Valemetostat - an approved dual EZH1/EZH2 inhibitor that has already worked in an MLL-AF4 xenograft, in a disease nobody has enrolled it in · Drug
- 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 · Drug
- Blinatumomab in infant KMT2A-rearranged ALL — the largest single outcome gain in thirty years · Drug
- Venetoclax in KMT2A-rearranged leukemia — the apoptotic partner every other drug needs · Drug
- AUGMENT-101 (NCT04065399) — the registration trial, and what 22.8% actually means · Trial
arises in · 7
- Monoblast — the immature monocyte that names FAB M5a, the dominant morphology of congenital KMT2A leukaemia · Cell type
- Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL · Cell type
- Fetal CD19+CD34+CD10-negative PreProB progenitor — a cell that exists before birth and almost not at all after · Cell type
- Lymphoid-primed multipotent progenitor (LMPP) — the bi-potent cell that explains how one fusion makes two lineages · Cell type
- Haemogenic endothelium — the vessel-wall cell that gives birth to blood · Cell type
- iALL-IRX1 — the HOXA-negative, IRX1-high state of infant KMT2A::AFF1 ALL · Cell state
- iALL-HOXA9 — the HOXA-high state of infant KMT2A::AFF1 ALL, and the one everything is modelled on · Cell state
inhibits · 5
- Correcting the fusion with genome editing: verdict NOT FEASIBLE for infant leukaemia, though intron-targeted disruption is a real published strategy · Target
- RNA-targeting the fusion transcript: verdict THE LEAST HOPELESS of the three fusion-level routes, blocked by delivery rather than by biology · Target
- JDI-12 - published as a JMJD1C inhibitor that preferentially kills KMT2A-rearranged leukaemia and spares cord blood, then used as 'KDM3i' to CREATE KMT2A rearrangements in cord-blood progenitors, by two papers that do not cite each other · Drug
- Silmitasertib (CX-4945) - a CKII inhibitor that works on KMT2A-rearranged leukemia by strengthening the allele the fusion does not have · Drug
- BET bromodomain inhibition in KMT2A-rearranged leukemia — spectacular preclinically, stalled clinically · Target
expressed in · 4
- 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 · Cell state
- ICOSLG on infant t(4;11) blasts converts T cells into regulatory T cells - the one immune-evasion route measured in this exact disease, in this exact age group · Mechanism
- SIT1 - one of only three surface proteins in the screen that is both expressed in KMT2A::AFF1 lines and absent from normal parenchyma, and it is clean because it is leukocyte-restricted, not because it is leukaemic · Gene
- S1PR4 - the third parenchymally clean surface protein in the screen, a leukocyte-restricted GPCR, and not fusion-specific either · Gene
KMT2A::MLLT3 (MLL-AF9), t(9;11)(p21.3;q23.3)
This is the same broken KMT2A gene as in infant leukemia, but joined to a different partner called AF9, and the combination produces myeloid leukemia rather than lymphoid. AF9 carries a small reading head that recognises chemical tags on chromatin and brings in an enzyme called DOT1L, so this version of the fusion has an extra, partly druggable step that the AFF1 version does not.
- sourced claims
- 6
- counter-arguments
- 7
- distinct sources
- 6 (6 papers)
- connections
- 126
established 3strong 3
related to · 63
- MLLT3 runs normal stem-cell self-renewal and is required in essentially no leukaemia line — the inverted case · Mechanism
- Repairing 85 defective citation blocks, and the finding that the queue's own numbers were wrong in three directions at once · Analysis
- Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents · Explainer
- Ordering the fusions developmentally — which stage of blood formation each one hijacks, and at what age the child presents · Explainer
- BRD4 — the best-drugged protein in this beat, and the one whose clinical result is already in and disappointing · Protein
- A 2026 preprint puts XPO1 upstream of the menin interface itself: XPO1 reported to stabilise menin on chromatin and menin's binding to KMT2A and KMT2A::MLLT3 · Mechanism
- An anti-MLL-N antibody sees the wild-type allele and the direct fusion, and nothing else - and cannot rank them · Explainer
- Anti-AF9 antibodies see three proteins, not two - and the third is an internal-promoter isoform discovered in 2025 · Explainer
- The KMT2A breakpoint cluster region: an 8.3 kb stretch built to break · Breakpoint
- Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1 · Mechanism
- DOT1L's localization record is a mouse kidney paper wearing a human label - and the one image of it in a leukaemia cell is a supporting figure a title search cannot see · Mechanism
- MLL-AF9 leukaemia destroys the nerves that run its own niche — a mechanism class this graph had nothing on · Mechanism
- HNF4A - a liver and pancreas nuclear receptor acting as the metabolic effector of TIFAB in KMT2A::MLLT3 AML, on a single paper · Protein
- KMT2A::MLLT1 versus KMT2A::MLLT3: paralogous partners whose chromosomes break on opposite sides of the same domain · Explainer
- Every human t(9;11) cell line, with every accession fetched and read back: eleven lines, ten patients, and two of them are B-ALL · Analysis
- KMT2A::MLLT3 / t(9;11): the best-known partner prognosis claim, and the three cohorts that did not reproduce it · Epidemiology
- DNA-PKcs phosphorylates AF9 at S395 and releases it from the super elongation complex - the only AF9 regulatory element the fusion keeps · Mechanism
- Four regulatory elements on AF9, and the fusion keeps exactly one - the phospho-switch that controls SEC binding · Analysis
- The AF9 acetylation arm: PCAF at K339, HDAC5 gated by CaMKII - a kinase-controlled switch the fusion throws away · Mechanism
- Skin first, blood later: a three-day-old referred for purple spots, with KMT2A::MLLT3 neonatal ALL · Patient story
- KMT2A-rearranged AML is two diseases on the phosphorylation layer, and DOT1L phosphorylation is one of the things that separates them · Analysis
- 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 · Mechanism
- EIF2AK3 / PERK (Q9NZJ5) - the kinase whose transcript is flat under both inhibitors, whose arm IS functionally required in MLL-AF9 leukaemia stem cells, and whose common name collides with phospho-ERK · Gene
- CBS (P35520) - the largest fall in the whole panel (-4.07), a token that collides with Cajal bodies AND CTCF binding sites, and a germline phenotype whose hallmark is thrombosis · Gene
- 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 · Analysis
- Asked for the first time whether a KMT2A fusion GAINS chromatin sites under a menin inhibitor: all three pre-registered criteria fire, and the set they fire on is 52 low-amplitude bins reaching 6x the genome median, 16 of them with no gene within 20 kb and 1 of 52 on a CpG island where 66% of the fusion's real sites are · Analysis
- A DOT1L inhibitor, which does not touch the menin-KMT2A interface, removes 70% of the fusion's enrichment from its own strongest sites - two thirds of what a menin inhibitor removes - so fusion chromatin residency is partly downstream of H3K79 methylation rather than only of menin · Analysis
- MOLM13 (KMT2A::MLLT3) is the only line in GSE127507 with a matched input in BOTH conditions, and it gives the one differential-input-controlled measurement in the series - MLL1-N occupancy at its own top 0.1% of bins is unchanged (share ratio 0.9438, input 0.9542, input-corrected 0.9891) with ZERO gained bins genome-wide, while menin retains only 13.0% of its own top windows · Analysis
- The four-way ordering given a second cell line: menin, DOT1L and the MLL1-N channel reproduce between KMT2A::AFF1 and KMT2A::MLLT3 to within 0.04 of a share ratio, and H3K79me2 - the one channel the ordering was built around - diverges by 0.21 to 0.30 and changes places with MLL1-N · Analysis
- The chromatin exchange at a menin-inhibited fusion site, measured in one experiment: H2AK119ub and H3K27me3 in, H3K4me3 out, in proportion to how much fusion left - and PCGF1 loss attenuates the in-fill without abolishing it · Mechanism
- In murine MLL-AF9, H3K79me2's response to a menin inhibitor runs 0.586 / 0.819 / 0.928 / 1.187 across the four eviction-depth quartiles of the fusion's own top-0.1% sites - Spearman -1.000, span 0.6005, the largest of any mark measured in these bins except H3K27me3 - while the aggregate over the same 1,228 bins is a single unremarkable 0.8156 · Analysis
- 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 · Hypothesis
- 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) · Mechanism
- The same-condition H2AK119ub noise floor in GSE260742 spans twentyfold across the deposit's three experimental arms - D1 |R-1| of 1.89% in the PCGF1-KO clone, 10.49% in the non-targeting control and 37.04% in the MLLAF9 Control arm - at one mark, one lab, one pairing shape and one external stratifier. A single same-condition floor for this deposit does not exist. · Analysis
- The GSE260742 H2AK119ub pair that shares a processing state - rep2 against rep3, both bare `.tdf` - is not an unconfounded replicate pair: rep3 was submitted 2024-10-01 and rep2 2024-03-03, through a different file-naming pipeline. No pairing in this deposit isolates replicate variance alone. · Analysis
- First deposit to put both drug classes on the MEN1 channel in one experiment: VTP-50469 leaves ZERO of the 19 DMSO menin peaks at 15 canonical menin-MLL target loci, while EPZ5676 keeps 14, compound 10 keeps 14 and compound 11 keeps 8 - strength-matched permutation p = 0.0003, and the zero is unchanged at every flank from 0 to 100 kb · Analysis
- The deposited RS4;11 H3K79me2 table in GSE149183 is two-thirds MOLM13: 38,580 of its 57,794 rows are byte-for-byte identical to the MOLM13 file, so the index fusion is measurable at only 19,214 TSS entries · Analysis
- RS4;11 retains 2.5x more H3K79me2 than MOLM13 under EPZ5676 at every one of ten baseline deciles - and 0.71x under compound 10, with the sign reversing in deciles 5-10: the between-line difference survives the baseline confound and fails the drug replication, so it cannot be attributed to the fusion partner · Analysis
- The CSF1R-positive fetal lymphoid-primed multipotent progenitor — a fetal-restricted subset of LMPPs that makes AML rather than ALL when KMT2A::MLLT3 is switched on, and exists in human embryos · Cell type
- Menin loses half its promoter signal where the fusion sat, and nothing where it did not · Analysis
- The stratification passes its own positive control: the fusion tag separates the two strata 62-fold · Analysis
- Summit containment passes the positive control that the bin-overlap measure failed, in all three HA batches · Analysis
- The menin inhibitor removes three-quarters of the fusion from its own promoters, replicated in two batches · Analysis
- Menin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled · Mechanism
- Menin does not outlast the fusion under revumenib in primary infant material - 0.586 against 0.485 at oncoprotein peaks, a ratio of 1.21 against a pre-registered threshold of 1.5 - so the fusion-independent menin plateau seen after a degron does not reproduce here · Analysis
- A menin inhibitor is not a fusion degron, so watching menin leave chromatin under one cannot identify what was holding it there - every model predicts the same result · Explainer
- GSE252378 fragment BEDs: a complete KMT2A N-terminal / C-terminal antibody set in 27 patient samples across six fusion partners, deposited and until now unopened by this corpus · Analysis
- PROM1 occupancy tracks HOXA at +0.93 in KMT2A::AFF1 and not at all elsewhere; it is near-absent in KMT2A-AF9 and -AFDN despite high HOXA · Analysis
- EPHA7 is the one core member with a published KMT2A::AFF1 promoter ChIP - and this beat's own data put it second on separation while denying it to the AF9 samples · Analysis
- AF9's nuclear residence is chaperone-dependent, the Hsp90 site is the SAME C-terminal region the fusion keeps, and UniProt records no cytoplasmic pool at all · Mechanism
- The pivotal menin-inhibitor paper reports that the drug does NOT globally displace MLL1 or the fusion from chromatin - menin goes, the fusion largely stays · Mechanism
- 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 · Gene
- IntAct curates 47 interactions against engineered MLL fusion proteins, and every accession-keyed query in this project is blind to all of them - while its PSICQUIC mirror stops at 2024 · Analysis
- t(9;11): the reciprocal product is made, is engineered into every genome-editing model, and has never been separately tested · Explainer
- GFI1 — the repressor that LSD1 inhibitors actually work through, and the scan hit whose literature points the opposite way · Protein
- Experiment: CRISPR knockout of CLEC12A in KMT2A-rearranged models, with and without a cooperating RAS lesion · Experiment
- 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 · Protein
- "Diverse models of MLL-rearranged leukaemia" is one mouse cell line: the RNF20 H2Bub requirement resolves to murine RN2 (MLL-AF9/NrasG12D) · Analysis
- The Mediator/BET deposition is 48 of 48 mouse MLL-AF9/NrasG12D samples: resolving the KMT2A status behind the MED23 verdict · Analysis
- The AHD inhibitor's deposited arm is MOLM-13 and its in vivo arm is nowhere: a half-resolution that names the limit exactly · Analysis
- KMT2A-rearranged or NPM1-mutant? Both, in separate arms: WT-MA9 mouse, MOLM13, OCI-AML3, and two patients on AUGMENT-101 · Analysis
- The unnamed osteolineage Cre is Prx1-Cre, which is not osteoblast-restricted - and that changes what the negative result means · Analysis
- The unnamed AML lines are NB4 and THP-1 - and NB4 is not KMT2A-rearranged at all · Analysis
depends on · 14
- 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 · Gene
- H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of · Mechanism
- KMT2A / MLL1 — the gene that breaks · Protein
- RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once · Protein
- EP300 — the acetyltransferase whose paralogue split is the finding: p300 is the 108th most KMT2A-selective gene, CBP is the 16,950th · Protein
- KDM1A (LSD1) — acts at the loci the fusion binds, spares normal stem cells, and still has never been shown to touch the fusion protein · Protein
- MYB — rank 17 of 17,728 for KMT2A selectivity, and the only node in this beat where partial, transient suppression eradicated leukaemia without stopping normal blood production · Protein
- Mechanism class 1 — chromatin and elongation hijack (KMT2A-r, NUP98-r) · Mechanism
- The strongest published case that condensates are load-bearing in KMT2A-fusion leukemia — and it is AKAP95, not AFF1 · Mechanism
- ACSL4 - a CRISPR-screen-derived, functionally validated KMT2A-selective vulnerability in myeloid disease, and a gene whose loss normally protects cells from ferroptosis · Protein
- MOF/KAT8 is required by both KMT2A::MLLT3 and NUP98::HOXA9 — which is why it is the wrong kind of convergence · Mechanism
- 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 · Gene
- 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 · Gene
- The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential · Mechanism
part of · 13
- The KMT2A::MLLT3 chimeric protein: what survives the join on each side, in residue numbers - and the four AF9 modules that do not · Protein
- Where t(9;11) actually breaks inside MLLT3: 98.4% downstream of exon 4, and the two patients in 442 who kept the reader · Breakpoint
- t(9;11) is the reciprocal-POSITIVE arm: 2 of 612 patients are spliced, against 241 of 460 for t(11;19) · Explainer
- 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 · Mechanism
- 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 · Explainer
- KMT2A::MLLT3 across 612 genotyped patients: myeloid at every age, but 248 of them have ALL, and 157 of those are infants · Epidemiology
- MLLT3 is the commonest partner in therapy-induced KMT2A leukaemia: 49 of 142, and 47 of those are t-AML · Epidemiology
- THP-1 (CVCL_0006): the default KMT2A::MLLT3 line, from a one-year-old, carrying NRAS G12D and a TP53 frameshift · Explainer
- Where KMT2A::MLLT3 sits in the nucleus: two papers, both overexpression, both from before 2005 - and the fusion carries no AF9 import signal · Mechanism
- BCOR, not CBX8, is the AHD contact MLL-AF9 cannot lose - and the same two partners bind ENL far more tightly than AF9 · Mechanism
- KOPB-26 (CVCL_7972): a t(9;11) B-ALL line from a 13-month-old, and the model for 42% of this partner's patients that nobody uses · Explainer
- Import class 1: murine MLL-AF9 myeloid transformation, the field's default assay and this graph's largest single import · Explainer
- 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 · Mechanism
refutes · 7
- 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 · Gene
- 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 · Gene
- Spliced KMT2A fusions: breaks upstream of the partner's exon 1, and the reciprocal-free natural experiment · Breakpoint
- 756 children with 11q23/MLL-rearranged AML: 5-year EFS runs from 11% to 92% depending on the partner · Epidemiology
- 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 · Analysis
- 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 · Analysis
- 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 · Mechanism
binds · 5
- 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 · Gene
- GATAD2A / p66-alpha (Q86YP4) - the subunit that bridges NuRD's two modules, the best-ranked NuRD gene in this project's KMT2A-selectivity scan, and present in the pan-fusion interactome under MLL-AF9 but NOT the index fusion · Gene
- SIN3A (Q96ST3) - the scaffold of the OTHER HDAC1/2 corepressor complex, a 5' fusion partner in infant B-ALL and in myelodysplasia, and present in three MLL-fusion AP-MS columns but not the index fusion's · Gene
- ARID4B / SAP180 (Q4LE39) - the Sin3A-complex subunit that shares SIN3A's HDAC1-binding region, is in the MLL-fusion interactome, and is the second of only two epigenetic vulnerabilities a CRISPR screen found in KMT2A-rearranged ALL · Gene
- 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 · Gene
tests · 5
- SMC3 - the cohesin ATPase arm, the only subunit whose partial loss has been tested directly against a KMT2A fusion, and it was tolerated · Gene
- In-silico digest of 81 modelled KMT2A fusion junctions: the peptide that would prove the fusion protein exists · Analysis
- Knock S395A into the MLLT3 half of a KMT2A::MLLT3 model and ask whether it becomes chemotherapy-resistant · Experiment
- PROPOSED: swap the partner, hold everything else - KMT2A::MLLT3 versus KMT2A::AFF1 in LIN28B-null human fetal liver CD34+ cells · Experiment
- The positive control this corpus has never had: degrading MLL::AF9 clears its own tag from 93-97% of its strongest chromatin sites within 3 hours, and two INDEPENDENT sequencing batches agree to within 4.6 points - the first technical noise floor ever measured for a ChIP eviction comparison in this project · Analysis
supports · 4
- The CRISPR-ChIP H3K79 partition is a mouse MLL-AF9 result: resolved from GEO after the full text proved unreachable · Analysis
- 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 · Analysis
- CBX5 / HP1-alpha (P45973, 191 aa) - the H3K9me3 reader that recruits the writer, the writer's destroyer and the second writer; and the one member of that circuit with a published pro-leukaemic role, as part of an MLL leukaemia stem-cell programme that immortalises myeloid progenitors WITHOUT Hoxa or Meis · Gene
- AKAP95 IDR1 co-condenses with the KMT2A N-terminal fragment - the one AKAP95 contact that lands inside the region every KMT2A fusion retains · Interface
treated by · 4
- CK2 phosphorylates KMT2A at T2724/S2726 to license taspase1 cleavage - and that site is in the half the fusion throws away · Mechanism
- VTP-50469 - the preclinical menin-KMT2A interface inhibitor that almost every chromatin experiment in this field actually used, and which had no entry of its own in this graph · Drug
- Scored against the same DMSO in the same batch, degrading the fusion leaves 1.0% of its chromatin sites, the DOT1L+menin combination leaves 10.7%, the menin inhibitor alone leaves 51.7% and the DOT1L inhibitor alone 75.5% - and in a second independent batch the menin inhibitor again beats the DOT1L inhibitor on the fusion's own channel · Analysis
- JD-PI95 - a genetically encoded bridging peptide that drags AKAP95 to HSP70 and dissolves its condensates, with in vivo activity in THP-1 · Drug
analogous to · 3
- KMT2A::MLLT1 (MLL-ENL), t(11;19)(q23;p13.3) · Fusion
- Partner import: when a mechanism measured in one fusion is asserted about another · Explainer
- 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 · Fusion
regulates · 3
- 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 · Gene
- Removing the fusion is a transcription event first and a chromatin event later, and the gap is enormous: nascent transcription changes within 15 minutes, while genome-wide RNA Pol II peak calls are 99.6% retained at 3 hours and not one active histone mark loses a peak call by 24 hours - the fusion's immediate job is licensing elongation, not building a chromatin landscape · Mechanism
- MECOM (EVI1) - a cell-of-origin memory that MLL-AF9 maintains but cannot install, present in about 43% of MLL-rearranged AML and marking the chemoresistant half · Gene
causes · 2
confers resistance to · 1