BCOR — the other side of the CBX8 conflict, and a target you would be inhibiting in the direction of disease

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• Directional risk, and the most serious one here: BCOR is understood as a recurrently lost, tumour-suppressor-like gene in other myeloid and lymphoid malignancies. A BCOR inhibitor would move cells in the direction a different leukemia's driver mutation moves them, and in a child cured of KMT2A-rearranged leukemia that is a second-malignancy hazard no proliferation assay detects. (Unverified this cycle; flagged rather than asserted.)
• Compensation: BCORL1 occupies the same PRC1.1 slot and is present in place of BCOR in the verified 5JH5 structure. A BCOR-selective drug is buffered by its paralogue, and a drug potent enough to hit both loses whatever selectivity the PRC1.1 argument was supposed to provide.
• Essential-function toxicity: gnomAD LOEUF 0.196 with 10 observed loss-of-function variants against 86.7 expected is among the most constrained profiles in this interactome, tighter than DOT1L or PSIP1, and HPA reports BCOR detected in all tissues. The reassuring DepMap mean comes from immortalised cancer lines and says nothing about human development or haematopoietic stem cells.
• Resistance is trivially available: DepMap says BCOR-null cells are not disadvantaged (mean +0.025), and the KMT2A::AFF1 line MV4-11 actually gains (+0.669). Under a BCOR-directed drug, selection for BCOR loss costs the leukemia nothing.
• Delivery and modality: there are zero verified small-molecule ligands of BCOR at any site. The contested interface is a 32-residue segment binding a domain that is disordered until it folds on binding, which is the hardest class of protein-protein interface to drug with a small molecule; the productive precedent on that surface is peptidomimetic (8TLV/8TLW/8TLX on the AF9 side), with the permeability and exposure problems that implies.
• BCOR is a target you would be inhibiting in the direction of disease, and there is now a dose-independent reason: loss of PRC1.1 subunits including BCOR confers MENIN-INHIBITOR RESISTANCE by reactivating non-canonical menin targets including MYC (PMID 39158067). In a disease whose leading agent is a menin inhibitor, a BCOR-directed agent would be phenocopying the resistance mechanism.
• There is a documented rescue, which is the useful half: PRC1.1-deficient leukaemia cells show reduced monocytic signatures and become susceptible to BCL2 inhibition, and venetoclax overcomes menin-inhibitor resistance in them (PMID 39158067). That makes BCOR/PCGF1 status a candidate biomarker for adding venetoclax rather than a target.
• Degrading BCOR does not clear the complex from chromatin - it uncouples it, producing a localised loss of H2AK119ub while the chromatin-binding moiety and H3K27me3 stay put (PMID 42273916). A degrader and an interface inhibitor would therefore not be equivalent, and neither would displace KDM2B from CpG islands.
• Essential-function toxicity in the normal stem-cell compartment: BCOR maintains primed pluripotency in human ESCs and its depletion initiates endoderm and mesoderm differentiation (PMID 29337181), while Bcor loss in murine HSCs expands myeloid progenitors and cooperates with KrasG12D to cause leukaemia (PMID 30902969). Removing BCOR is leukaemogenic in the cell type the drug would reach.

1. Does BCORL1 buffer BCOR loss in KMT2A-rearranged lines? The verified PRC1.1 structure 5JH5 contains BCORL1 in the slot that BCOR occupies in 8HCU, so a BCOR single knockout may be measuring redundancy rather than requirement. A BCOR/BCORL1 double knockout in MV4-11 and SEM would settle it, and MV4-11's +0.669 makes it the informative line.
2. Is the AF9-binding segment (1176-1207) or the PUFD (1634-1748) the right target? They are 400 residues apart, have different partners and different predicted toxicities, and no experiment reported in either conflicting paper distinguishes a BCOR-fusion-contact requirement from a PRC1.1 requirement.
3. Is BCOR genuinely a recurrent loss-of-function target in other leukemias? We could not verify this in this cycle, and it is the claim that most affects whether a BCOR-directed programme should start at all — a documented tumour-suppressor pattern would invert the therapeutic-window argument.
4. Why does MV4-11, a KMT2A::AFF1 line, grow measurably better without BCOR (+0.669) when a KMT2A::MLLT3 line like NOMO-1 grows worse (-0.361)? If that split is reproducible it is a fusion-partner-dependent effect, which is exactly the kind of structure this project is looking for — and it is invisible in the mean.
5. Are the AF9 AHD interface mutants used in PMID 32954361 BCOR-selective, or do they also perturb DOT1L and AFF1/AF4 binding to the same folds-on-binding surface? The same question is open for the CBX8 mutants in PMID 22094252, and answering it for both sets is the cheapest route out of the conflict.
6. Does the KMT2A fusion sit at the same CpG islands that KDM2B directs PRC1.1 to? BCOR binding to MLL-AF9 is essential for leukaemia (this entry's E2) and BCOR's address is supplied by the KDM2B CxxC domain - and this graph separately holds localization-cxxc-cpg-address for the fusion's own CxxC. Two CxxC-directed complexes reading the same islands is a testable model and no one has run the overlap.
7. Is the PRC1.1 differentiation restraint present in KMT2A-rearranged B-lineage disease, or only in AML? Every PRC1.1 degron result is myeloid, and in KMT2A-rearranged ALL menin inhibition kills rather than differentiates, so the PRC1.1 arm may not behave the same way.
8. Does BCOR loss change H2AK119ub at HOXA specifically in a KMT2A-rearranged cell? Bcor loss derepresses Hoxa7/Hoxa9 in normal murine HSCs, where those genes are off; in the index disease they are already on, so the same lesion may have no room to act.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   BCOR is not DepMap common-essential; mean Chronos across 1,208 lines is +0.025 with 2.2% of lines depleted, the leukemia mean is -0.060, the 10 KMT2A-rearranged lines average +0.003 and the 4 KMT2A::AFF1 lines +0.048, giving selectivity_vs_leukemia +0.063 and selectivity_vs_all_lines -0.022; the KMT2A-rearranged spread runs from NOMO-1 at -0.361 to MV4-11 (a KMT2A::AFF1 line) at +0.669; gnomAD gives pLI 1.0, LOEUF 0.196, 10 observed versus 86.7 expected loss-of-function variants and mis_z 2.16; HPA classifies BCOR as low tissue specificity, detected in all tissues, low immune cell specificity, nucleoplasmic.

   DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API; loss-of-function constraint via the gnomAD GraphQL API; normal-tissue expression via the Human Protein Atlas API · Broad Institute DepMap; gnomAD; Human Protein Atlas; Open Targets Platform · Databases 2026
   ▸What this evidence cannot show

   Means were computed by us from per-line API values rather than read from a DepMap release table, and the API does not state the release version. Only 10 KMT2A-rearranged lines (4 KMT2A::AFF1) contribute; a selectivity of +0.063 is well inside the noise band (any absolute value under 0.15 at n=10) and the per-line spread from -0.361 to +0.669 means even the sign of the leukemia comparison is unstable. Whole-gene knockout of a 1,755-residue protein removes the BCL6-binding domain, the AF9-binding segment and the PRC1.1 PUFD at once and therefore cannot test any one of them. The paralogue BCORL1 occupies the same PRC1.1 slot, so a single-gene knockout is a buffered experiment. Cell lines are not normal tissue, and a chronic three-week proliferation readout cannot see a requirement at transformation.

   ▸Evidence that argues against this (1)

   • Schmidt et al. 2020 report that BCOR binding to MLL-AF9 is essential for leukemia via altered EYA1, SIX and MYC activity. If correct, the flat DepMap profile reflects BCORL1 buffering, the transformation-versus-maintenance distinction, or the fact that whole-gene knockout is not the same perturbation as an interface mutant. Schmidt CR et al. 2020
2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   BCOR binding to MLL-AF9 is essential for leukemia and acts through altered EYA1, SIX and MYC activity, whereas disrupting direct CBX8/MLL-AF9 binding does not affect proliferation; the BCOR 1176-1207 segment bound to the MLLT3/AF9 ANC1 homology domain 500-568 is solved as 6B7G.

   BCOR binding to MLL-AF9 is essential for leukemia via altered EYA1, SIX, and MYC activity · Schmidt CR, Achille NJ, Kuntimaddi A, et al. · Blood Cancer Discovery 2020
   PMID 32954361DOI
   ▸What this evidence cannot show

   Confidence is downgraded to moderate because DepMap does not support the positive claim: BCOR knockout is not anti-proliferative in any context measured (mean +0.025, KMT2A-rearranged mean +0.003). The system is MLL-AF9, not KMT2A::AFF1. The decisive experiments are AF9 AHD interface mutants, and because all four AHD partners share one surface that folds on binding, a mutation chosen to abolish BCOR binding may also perturb DOT1L or AFF1/AF4. The abstract reports no affinity measurement, so no Kd is attributed to 6B7G. The EYA1/SIX/MYC mechanism is reported for this system only and is not extended here to KMT2A::AFF1.

   ▸Evidence that argues against this (1)

   • Tan et al. 2011 report the opposite assignment on the same AHD: that CBX8 is the essential partner and that MLL-AF9 mutants losing CBX8 binding cannot transform. The two papers cannot both be right about which arm of the hub matters. Tan J et al. 2011
3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   Verified BCOR structures cover three non-overlapping regions of the 1,755-residue protein with no structure containing more than one: the BBD peptide 498-514 with the BCL6 BTB domain (3BIM, X-ray 2.60 A), the AF9 AHD-binding segment 1176-1207 on MLLT3 AHD 500-568 (6B7G, NMR), and the PUFD 1634-1748 alone (2N1L, NMR), with the PCGF1 RAWUL domain 167-255 (4HPL, X-ray 2.00 A) and in the PRC1.1 ternary complex with PCGF1 151-255 and KDM2B 1103-1336 (8HCU, X-ray 2.20 A).

   RCSB PDB entries 3BIM, 6B7G, 2N1L, 4HPL and 8HCU, with per-entity UniProt accessions and modelled residue ranges resolved against the RCSB search and data APIs · RCSB Protein Data Bank · RCSB PDB 2026
   ▸What this evidence cannot show

   Identifiers, resolutions and residue ranges were resolved against the RCSB API in this session; ranges are RCSB's UniProt-mapped modelled segments rather than independently curated domain boundaries. Because no structure spans two of the three regions, nothing here constrains their relative arrangement in the intact protein, and the 1,427 residues between the BBD and the PUFD are structurally uncharacterised. 8HCU comes from a calcium/liquid-liquid-phase-separation study (PMID 39256555) and is cited here for the structure only. None of these entries carries a published affinity in the abstracts verified, so no Kd is populated.

   ▸Evidence that argues against this (1)

   • Counting PDB entries measures how tractable a protein was to CRYSTALLISE, which correlates with being small, ordered and well-behaved rather than with being druggable. What decides design value is whether the deposited density covers the site that matters, at a resolution that supports modelling, in the relevant state — and this graph has repeatedly found structures described in the direction that overstates what is resolved. Three non-overlapping regions of a 1,755-residue protein with no structure containing more than one means there is no model of how the regions are arranged relative to each other, which is exactly what a bivalent or degrader strategy would need. RCSB PDB 2026
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   The KDM2B-PCGF1-SKP1 non-canonical PRC1.1 crystal structure 5JH5 (X-ray 2.55 A) contains BCORL1 residues 1668-1785, not BCOR, and KDM2B recruitment of PRC1.1 requires cooperation between PCGF1 and BCORL1.

   KDM2B recruitment of the Polycomb group complex, PRC1.1, requires cooperation between PCGF1 and BCORL1 · Wong SJ, Gearhart MD, Taylor AB, et al. · Structure 2016
   PMID 27568929DOI
   ▸What this evidence cannot show

   This is cited here principally as a correction: 5JH5 is frequently miscredited to BCOR. It also carries the redundancy warning that matters for interpreting the DepMap knockout, because BCORL1 can occupy the PRC1.1 slot that BCOR occupies in 8HCU. The paper does not study KMT2A fusions and says nothing about the AF9 AHD.

   ▸Evidence that argues against this (1)

   • The entry states the disqualifying detail and it deserves the weight: 5JH5 contains BCORL1, not BCOR. Substituting a paralogue's structure for the protein under discussion is how a dossier ends up asserting an interface that was never solved for the molecule in question. RCSB PDB 2026
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   ChEMBL v34 has no single-protein target for BCOR; the only record is the protein-protein-interaction target CHEMBL4106125 (BCoR-BCL6) with 9 activity rows, best CHEMBL4075278 at IC50 100 nM, and that chemistry is BCL6-BTB-groove-directed rather than BCOR-directed.

   ChEMBL database version 34, protein-protein-interaction target CHEMBL4106125 (BCoR-BCL6): target_search, get_bioactivity and get_mechanism queries, and the absence of any single-protein BCOR target · EMBL-EBI ChEMBL · ChEMBL 2026
   ▸What this evidence cannot show

   The 9 rows must not be counted as BCOR ligandability: the compounds bind the BCL6 BTB groove and use displacement of the BCOR BBD peptide only as a readout. This is the same class of error as the molibresib chemoproteomic artifact that inflates apparent ligandability for AFF1, AFF4, ELL, PAF1, SETD1A and ASH2L in this interactome. Nothing in ChEMBL addresses BCOR residues 1176-1207 or the PUFD. Counts are page-local under a 25-row API limit, and absence from ChEMBL is not absence from the world, though for a protein with no single-protein target it is close.

   ▸Evidence that argues against this (1)

   • A ChEMBL activity-row count measures how much medicinal chemistry has been DONE, not how tractable the target is, and the best reported affinity belongs to the most optimised compound in whichever series someone chose to pursue. Zero rows means nobody tried; thousands of rows means a target had a decade of industrial attention. A protein-protein-interaction target whose chemistry is aimed at BCL6 tells you about BCL6 programmes, not about BCOR tractability. ChEMBL, EMBL-EBI 2026
6. E_q66_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   BCOR's genomic address is supplied by two recruitment routes in one complex: BCOR complex components and mono-ubiquitylated H2A localise to BCL6 TARGETS, and the same complex contains FBXL10/JHDM1B - the CxxC-domain protein now called KDM2B - alongside RING1, RYBP, NSPC1 and RNF2, so BCOR brings two classes of E3 ubiquitin ligase and a histone demethylase to chromatin; the same work records that BCOR suppresses the transcriptional activity of AF9, a common mixed-lineage leukaemia fusion partner.

   Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets. · Gearhart MD; Corcoran CM; Wamstad JA; Bardwell VJ · Mol Cell Biol 2006
   PMID 16943429DOI
   ▸What this evidence cannot show

   Biochemical purification and chromatin immunoprecipitation in cultured human cells, not leukaemia and not a KMT2A-rearranged system. This is a genomic-address result, not a compartment result: it says which loci BCOR occupies, and says nothing about nuclear bodies, condensates or fractions. The KDM2B subunit was called FBXL10/JHDM1B at the time and its H3K36 demethylase activity had just been reported, so the CpG-island targeting that this graph attributes to the CxxC domain is a later synthesis. Read: abstract only. Identifiers copied field by field from the efetch record fetched 2026-09-21, ArticleId anchored per brief rule 81.

   ▸Evidence that argues against this (1)

   • A degron experiment shows BCOR is not the address but the BRIDGE, which changes what a BCOR localisation claim means: BCOR is a bridging factor tethering the catalytic and chromatin-binding moieties of PRC1.1, and BCOR degradation induces a QUICK LOCALISED loss of H2AK119ub at PRC1.1 target genes while PRC2-deposited H3K27me3 is unaffected. Removing BCOR therefore uncouples the complex rather than displacing it wholesale, and the residual chromatin-binding moiety stays put. Mojallali F; De Meis A; Alkema SG; Atsma TJ; Hogeling SM; Kloosterman R; Ioannou E; Wierenga ATJ; Huls G; Martens JHA; Schuringa JJ; van den Boom V 2026
7. E_q66_cell1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In mouse, BCOR inactivation in HAEMATOPOIETIC STEM CELLS expands myeloid progenitors and cooperates with oncogenic KrasG12D to initiate an aggressive, fully transplantable acute leukaemia, with differential regulation of a subset of PRC1-target genes including the HSC-associated transcription factors Hoxa7 and Hoxa9.

   Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis. · Kelly MJ; So J; Rogers AJ; Gregory G; Li J; Zethoven M; Gearhart MD; Bardwell VJ; Johnstone RW; Vervoort SJ; Kats LM · Nat Commun 2019
   PMID 30902969DOI
   ▸What this evidence cannot show

   A conditional mouse model mimicking the mutations seen in human haematological malignancies - murine, myeloid, and a loss-of-function lesion cooperating with RAS, which is the opposite polarity from the KMT2A-fusion context where BCOR binding to the fusion is required. Claim written with the system first per brief rule 73. Hoxa7/Hoxa9 derepression on BCOR loss is the mechanistic overlap with this graph's index disease and is also the point of maximum confusion, because in KMT2A-rearranged leukaemia those genes are already on. Read: abstract only.

   ▸Evidence that argues against this (1)

   • The polarity inverts in KMT2A-rearranged AML under a menin inhibitor, which is the setting this graph cares about: loss of PRC1.1 subunits such as PCGF1 or BCOR causes menin-inhibitor RESISTANCE by epigenetically reactivating non-canonical menin targets including MYC, and those PRC1.1-deficient cells show reduced monocytic gene signatures and become susceptible to BCL2 inhibition, with venetoclax overcoming the resistance. So BCOR loss is leukaemogenic in one context and drug-resistance-conferring in another, and neither makes BCOR a target you would inhibit. Zhou X; Zhang L; Aryal S; Veasey V; Tajik A; Restelli C; Moreira S; Zhang P; Zhang Y; Hope KJ; Zhou Y; Cheng C; Bhatia R; Lu R 2024
8. E_q66_cell2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Sustained PRC1.1 activity restrains leukaemic cell differentiation, and it does so independently of the canonical PRC2 axis: leukaemic stem cell viability in BCOR wild-type AML strongly depends on PRC1.1 activity; degron depletion of BCOR or KDM2B induces rapid time-dependent transcriptional induction; JARID2/AEBP2 and SUZ12 knockout cells devoid of PRC2.2 or of PRC2.1/PRC2.2 RETAIN PRC1.1-loss-induced transcriptional activation; and combined targeting of PRC1.1 and PRC2 induces DIFFERENTIATION of leukaemic cells.

   Sustained PRC1.1 activity preserves gene repression independently of PRC2.2 and restrains leukemic cell differentiation. · Mojallali F; De Meis A; Alkema SG; Atsma TJ; Hogeling SM; Kloosterman R; Ioannou E; Wierenga ATJ; Huls G; Martens JHA; Schuringa JJ; van den Boom V · Nucleic Acids Res 2026
   PMID 42273916DOI
   ▸What this evidence cannot show

   Human AML degron models; KMT2A status of the lines is not stated in the abstract, so this is an AML result and not an index-disease one. The differentiation readout comes only from the COMBINED PRC1.1-plus-PRC2 perturbation, so PRC1.1 loss alone is shown to induce transcription, not to induce differentiation. 'Strongly depends' for LSC viability is asserted as background rather than measured here. Read: abstract only.

   ▸Evidence that argues against this (1)

   • The same dependency runs in normal developmental contexts, which removes the window: BCOR is critical for maintaining PRIMED PLURIPOTENCY in human embryonic stem cells, and BCOR depletion there erodes Polycomb domains at key developmental loci and initiates endoderm and mesoderm differentiation. A PRC1.1-directed agent would be acting on a module that restrains differentiation in leukaemia and in normal stem cells by the same mechanism. Wang Z; Gearhart MD; Lee YW; Kumar I; Ramazanov B; Zhang Y; Hernandez C; Lu AY; Neuenkirchen N; Deng J; Jin J; Kluger Y; Neubert TA; Bardwell VJ; Ivanova NB 2018

• ← bindsPCGF1 — the PRC1.1 scaffold whose LOSS causes menin-inhibitor resistance, so it is a restraint on the leukaemia rather than a dependency of it

  PCGF1 RAWUL (aa 167-255) binds the BCOR PUFD domain; the interface that defines PRC1.1 (crystal structure)

• ← related toRNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once

  BCOR loss lowers RING1B protein and reduces H2AK119ub upstream of upregulated HoxA genes

• ← related toBCORL1 — 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

  paralogues that are NOT interchangeable: BCORL1 PUFD assembles with KDM2B alone, BCOR PUFD does not

• ← part ofPRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion

  corepressor arm; the subunit named in the KMT2A-rearranged menin-resistance screens

• binds →MLLT3 / AF9 — a famous fusion partner that is not a dependency, and a hub domain that is

  competes for the same AF9 surface as CBX8

• ← related toPhase-2 dossier: CBX8 - the candidate this review would kill, and the reasons are all numeric

  the published CBX8/BCOR tension that makes the direction of any CBX8 intervention uncertain

• ← related toA menin inhibitor does not only take something away - it causes PRC1.1 to put something on, and the drug needs the cell's own silencing machinery to work

  BCOR and BCORL1 are on routine myeloid panels, so this biomarker is retrospectively testable today

• ← related toWhat fills the space: RING1B and BCOR arrive at the fusion's sites under BOTH drugs, but the DOT1L inhibitor puts them everywhere on the fusion's territory while the menin inhibitor puts them only in the quartile where the fusion is most completely evicted - and at Meis1 RING1B rises 16-fold

  BCOR share rises 1.27-1.44x under VTP50469 and 1.68-1.91x under SGC0946 at fusion-held sites

• ← related toTwo processing batches inside one GEO series: the FLAG and KDM2B tracks put 1.7-1.9% of their coverage in ENCODE blacklist regions and the BCOR, RING1B and input tracks put 14-46%, with a single 2 kb bin at chr2:98,666,000 carrying 18.1% of the BCOR SGC0946 track on its own

  13.7-18.1 percent of each deposited BCOR track sits in one blacklisted 2 kb bin

• ← related toPrediction 5 of hyp-q117 contains three separable claims - normal eviction, no silencing, and return on withdrawal - and the deposit it names supports one of them only through a clause it never states; the eviction and silencing clauses need tracks the NTvKO arm does not carry, and withdrawal is absent from all 158 samples

  prediction 5 names a PCGF1 OR BCOR knockout; GSE260742's NTvKO arm is PCGF1 only, so the BCOR half of the prediction is untouched by this deposit

• ← related tohyp-q117's prediction 5 says 'in a PCGF1 OR BCOR knockout' and GSE260742's only genetic perturbation is the PCGF1 knockout: across all 158 sample records the strings BCOR, BCORL1, KDM2B, RING1 and RNF2 appear zero times as a perturbation, so a verdict on PCGF1 is not a verdict on the prediction as written

  the untested disjunct of prediction 5

• ← related toA cell that cannot deposit H2AK119ub is still evicted normally by a menin inhibitor and silences its vacated sites less - so a fusion-occupancy pharmacodynamic marker reads FULL ENGAGEMENT in exactly the genotype that responds worst, and this is now the fourth independent reason this corpus distrusts its own candidate markers

  the recurrent clinical version of the same complex deficit; untested

• part of →The CXXC domain (aa 1147-1195, PDB 2KKF) is a chromatin address, not a compartment address — CpG mutants lose transformation but keep their subnuclear position

  BCOR's address is read by the KDM2B (FBXL10/JHDM1B) CxxC domain in the same complex, with BCOR bridging the catalytic and chromatin-binding moieties - degrading BCOR strips H2AK119ub locally while the address itself stays occupied

• regulates →The state under menin inhibition — differentiation in AML, rapid death in ALL, and a GMP-like exit in the cells that switch lineage instead

  loss of PRC1.1 subunits including BCOR confers menin-inhibitor resistance by reactivating non-canonical menin targets including MYC; the resistant cells lose monocytic signature and become venetoclax-susceptible

• regulates →The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia

  sustained PRC1.1 activity restrains leukaemic differentiation independently of PRC2.2, and only COMBINED PRC1.1 and PRC2 targeting induces differentiation - PRC1.1 loss alone induces transcription, not differentiation

• regulates →Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here

  Bcor inactivation in murine HSCs expands myeloid progenitors and cooperates with KrasG12D to initiate transplantable acute leukaemia, with Hoxa7/Hoxa9 among the derepressed PRC1 targets

• regulates →MYC - named in a hundred entries of this graph and, until now, written in none

  MYC is a non-canonical menin target held down by PRC1.1; BCOR or PCGF1 loss reactivates it epigenetically and that reactivation is what makes the cells menin-inhibitor resistant

• ← bindsRYBP - the subunit that makes a variant PRC1 complex catalytically active, named by two entries in this graph and never written

  co-purified in the BCOR complex that suppresses AF9 transcriptional activity

• ← depends onMYC reactivation through PRC1.1 loss — a named, druggable bypass out of menin dependence

  loss of the PRC1.1 subunit BCOR (or PCGF1) is the initiating lesion