MEN1 / menin — the adaptor the fusion cannot work without

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.

• Resistance: MEN1 interface mutations arise under single-agent pressure and preserve MLL1 binding, so the fusion program restarts while the drug still occupies nothing.
• On-target endocrine toxicity: hyperparathyroidism is already on the revumenib label at 2.5 months of exposure; the neoplastic risk over years is untested rather than excluded.
• Essential-function toxicity: menin is required for long-term HSC function under stress, so haematopoietic recovery after intensive therapy may be impaired in a way that is hard to attribute.
• Differentiation syndrome is a mechanism-linked, potentially fatal toxicity that scales with how well the drug works.
• Localisation bite-back: if the drug's measured effect on menin is partly DEGRADATION rather than eviction (PMID 31497350), pharmacodynamic assays reading menin occupancy will over-report target engagement wherever menin turnover differs - and an interface mutation that preserves menin levels while preventing eviction (PMID 36922589) will look like a pharmacokinetic failure rather than a resistance mechanism.
• The 'menin is not parathyroid-enriched' reassurance carries no information: menin is not enriched in any tissue. The dosage-sensitive elements of the module are MLL, p27 and p18, and in mouse they are endocrine-predominant - so the tissue most exposed to partial disruption is the one where the module already runs highest, which is the opposite of what the expression argument implies.
• A company is developing menin-MLL inhibition deliberately to release the endocrine G1 restraint and regrow beta cells. The leukaemia drug releases the same restraint in the same way. The therapeutic and the toxic use are the same intervention on the same cell state in two different glands, separated only by duration.

1. Does ziftomenib raise intact parathyroid hormone when it is actually measured? This single experiment separates a class effect from a compound-specific one.
2. Is the revumenib hyperparathyroidism signal reversible on drug withdrawal, and does it progress with longer exposure in the maintenance trials?
3. Is menin loss ever leukemogenic in its own right? If so, inhibiting a tumour suppressor in the treated lineage is the most dangerous unexamined risk in this programme.
4. Neither revumenib nor ziftomenib has had a carcinogenicity study, and both 13-week repeat-dose studies produced multi-organ lymphoma in one animal. Is that parallel finding in two structurally distinct inhibitors coincidence?
5. Where does menin go when a menin inhibitor evicts it from chromatin? Nobody has imaged it in any system. An endogenous-tag menin line imaged under revumenib, with total menin protein measured in the same cells, separates eviction from degradation - which no published experiment does.
6. Is menin chromatin-bound independently of KMT2A? Menin CUT&RUN in a KMT2A-degron line, read at the earliest timepoint after degradation, would settle a premise this graph has relied on without evidence in either direction.
7. Was parathyroid in the panel of the one study that measured the module's tissue distribution (PMID 22037578)? If MLL, p27 and p18 are endocrine-predominant but parathyroid was never measured, the tissue with the clinical signal is absent from the only evidence on tissue selectivity.
8. Which methylation state does menin direct at CDKN1B and CDKN2C? Both founding papers say only 'H3 lysine 4 methylation'. me1 at distal elements and me3 at the TSS would be differently sensitive to a menin inhibitor, and the answer decides whether the endocrine arm is expected to move under drug at all.
9. Does KMT2B rather than KMT2A carry menin's Hox footprint? Menin is required for the overwhelming majority of H3K4 methylation at Hox and MLL1 for only a subset; if KMT2B is the residual, a menin inhibitor is a broader chromatin intervention than the fusion-centric account implies, and it shares the menin-binding motif.
10. Do the two pharmacological measurements of the CDK-inhibitor arm disagree because of tissue, or because one of them is indirect? CDKN1A/1B/2C fall in human beta cells and p27 rises in osteosarcoma. Two Westerns in one laboratory across an endocrine and a non-endocrine line would settle it.
11. Does a menin inhibitor move the HSC quiescence set-point? The normal-blood liability is impaired recovery under stress, stress recovery is cell-cycle re-entry, and MLL1 is the maintainer of that set-point in the normal stem cell. No compartment-resolved cell-cycle readout under a menin inhibitor has been reported.

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

   MEN1 is not DepMap common-essential (mean Chronos about -0.36 across 1,258 lines) but is selectively depleted in KMT2A-rearranged and NPM1-mutant leukemia lines; MEN1 shows strong gnomAD LoF constraint (pLI ~1.0, LOEUF 0.204) and is not parathyroid-enriched (~6.8 nTPM); CDK9, PRMT1, ELL, WDR5, RBBP5, BRD4, SETD1A, CTR9 and PAF1 are common-essential.

   DepMap CRISPR (Chronos) gene effect, gnomAD constraint and Human Protein Atlas expression, retrieved via the Open Targets Platform GraphQL API, the gnomAD GraphQL API and the HPA API · Broad Institute DepMap; gnomAD; Human Protein Atlas; Open Targets · Databases 2026
   ▸What this evidence cannot show

   Per-line Chronos values were retrieved through the Open Targets API and the means were computed by us, not taken from a DepMap release table; the DepMap release version is not stated in the API response and remains unverified. Cell-line essentiality is a poor model of normal tissue tolerance. The leukemia subset is only 57 lines. HPA and GTEx disagree on tissue coverage and GTEx has no parathyroid tissue at all.

   ▸Evidence that argues against this (1)

   • Menin is required for long-term HSC function under competitive transplantation stress, so a low mean Chronos score should not be read as 'menin is dispensable in normal blood'. Maillard I et al. 2009
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Menin and MLL1 are genetically separable in normal haematopoiesis, with no genetic interaction in steady-state or regenerative haematopoiesis or B-cell differentiation, supporting menin-MLL1 disruption as a selective strategy.

   Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells · Li BE, Gan T, Meyerson M, Rabbitts TH, Ernst P · Blood 2013
   PMID 23908472DOI
   ▸What this evidence cannot show

   Mouse genetics with complete gene deletion, which models a drug only loosely; a conditional knockout is not the same as partial reversible occupancy, and the reassuring result may not transfer across species or to long-term dosing.

   ▸Evidence that argues against this (1)

   • Genetic separability in NORMAL mouse haematopoiesis is the right experiment for this question and bounds it narrowly: no genetic interaction in steady state, regeneration or B-cell differentiation says the two are separable in mouse blood, not that menin-MLL1 disruption is selective in a human patient whose other menin functions — endocrine, JUND-associated — are not tested by that design. Nature 2012
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Conditional menin loss in mouse haematopoiesis preserves steady-state multilineage and myelo-erythroid progenitor numbers but reveals a marked long-term HSC defect on competitive transplantation.

   Menin regulates the function of hematopoietic stem cells and lymphoid progenitors · Maillard I, Chen YX, Friedman A, et al. · Blood 2009
   PMID 19228930DOI
   ▸What this evidence cannot show

   Complete genetic deletion in mouse; competitive transplantation is a severe stress test that may overstate what partial pharmacological inhibition does in a patient.

   ▸Evidence that argues against this (1)

   • A long-term HSC defect revealed only under competitive transplantation describes a reserve that steady-state haematopoesis does not draw on. Patients on menin inhibitors after intensive chemotherapy and often after transplant are closer to the competitive condition than to steady state, so this is the result most likely to matter and least likely to be caught by routine counts. Journal of Clinical Oncology 2025
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.review

   Germline MEN1 loss causes multiple endocrine neoplasia type 1, with age-related penetrance above 50% by age 20 and 95% by age 40, primary hyperparathyroidism in essentially all patients by age 50 and typical onset at ages 20-25.

   Multiple Endocrine Neoplasia Type 1 (GeneReviews) · Giusti F, Marini F, Brandi ML · GeneReviews, University of Washington 2022
   ▸What this evidence cannot show

   Penetrance figures come from ascertained families and so are biased toward more severe phenotypes; this describes germline biallelic loss over decades, which is not the exposure a drug creates.

   ▸Evidence that argues against this (1)

   • A gnomAD constraint metric measures intolerance to heterozygous loss over a lifetime from conception, in a population sample. A drug gives partial reversible occupancy in an adult for weeks, so high constraint is not a safety signal for pharmacological inhibition. Penetrance above 50% by 20 and 95% by 40 describes decades of complete biallelic loss in a specific tissue lineage. The pharmacological analogue is weeks of partial occupancy, and this graph's endocrine beat has established that the two are not on one axis. gnomAD, Broad Institute 2026
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Somatic MEN1 mutations at the drug-menin interface cause clinical resistance to menin inhibition, and these mutants impair small-molecule binding while preserving the interaction with the natural ligand MLL1.

   MEN1 mutations mediate clinical resistance to menin inhibition · Perner F, Stein EM, Wenge DV, et al. · Nature 2023
   PMID 36922589DOI
   ▸What this evidence cannot show

   Describes acquired resistance in a relapsed/refractory population under single-agent pressure; the frequency of these mutations in frontline or combination settings is unknown. The specific residue list often quoted (M327I, G331R/D, T349M) is not enumerated in the abstract and should be read from the paper's figures before being asserted.

   ▸Evidence that argues against this (1)

   • Interface mutations are the best-characterised resistance mechanism and this graph now records that they are not the dominant one: resistance arises in patients with no prior menin-inhibitor exposure and with on-target repression preserved. An entry on the gene should carry both, because they point at different second-generation strategies. Nature 2023
6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   The revumenib US prescribing information lists hyperparathyroidism as an adverse reaction, with intact parathyroid hormone increased in 34% and corrected calcium increased in 15% of 241 patients at a median exposure of 2.5 months, while the ziftomenib label contains no parathyroid, PTH, calcium or other endocrine adverse-event terms.

   REVUFORJ (revumenib) and KOMZIFTI (ziftomenib) US prescribing information, retrieved via the openFDA drug label API · US Food and Drug Administration · openFDA 2026
   ▸What this evidence cannot show

   Label adverse-reaction rates are uncontrolled single-arm data in relapsed/refractory leukemia, where tumour lysis, renal impairment (creatinine increased in 38%) and heavy transfusion all move calcium, phosphate and PTH independently of the drug. The absence of endocrine terms in the ziftomenib label may mean the effect is absent or simply that intact PTH was not collected; these cannot be distinguished from the labels alone.

   ▸Evidence that argues against this (1)

   • Intact PTH raised in 34% at a MEDIAN EXPOSURE OF 2.5 MONTHS is the important qualifier. Parathyroid pathology in germline MEN1 develops over decades, so a 2.5-month window cannot bound what chronic dosing does — and infants treated frontline would be exposed for far longer than the label population was. U.S. Food and Drug Administration 2026
7. E_q72_men1_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   IN HUMAN CELLS BY THREE INDEPENDENT METHODS IN ONE 1998 PAPER - immunofluorescence, Western blotting of subcellular fractions, and enhanced-GFP epitope tagging - menin is located PRIMARILY IN THE NUCLEUS, and EGFP-tagged deletion constructs identify AT LEAST TWO INDEPENDENT NUCLEAR LOCALIZATION SIGNALS, both in the C-terminal fourth of the 610-residue protein. Of 68 known disease-associated MEN1 mutations, none of the 22 missense and 3 in-frame deletions touches either putative NLS, while none of the 43 frameshift/nonsense products would retain both.

   Menin, the product of the MEN1 gene, is a nuclear protein. · Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS, Chandrasekharappa SC · Proc Natl Acad Sci U S A 1998
   PMID 9465067DOI
   ▸What this evidence cannot show

   Abstract read in full; full text not read. NOT A LEUKAEMIA SYSTEM and not a haematopoietic one - this is the MEN1 endocrine-tumour literature, in transfected lines plus endogenous staining (brief rule 73). 'Primarily nuclear' is a partition statement, not an exclusion: the paper does not exclude a minor cytoplasmic pool and no later study this beat found has quantified one. The NLS mapping is by deletion construct, so it localises a sufficient region rather than a necessary signal. AND THE POINT THAT MATTERS FOR THIS GRAPH: UniProt O00255 does not cite this paper for the location (see E_q72_men1_loc5).

   ▸Evidence that argues against this (1)

   • The functional follow-up substantially weakens the naive reading of an NLS. Point mutations in NLS1, NLS2 and a third accessory signal NLSa DO NOT BLOCK nuclear translocation of menin at all - they compromise transcriptional output instead. So 'menin has two NLSs' overstates what the signals do: the 1998 deletion constructs removed enough sequence to abolish import, but the residues that make those regions NLS-like are dispensable for import in the 2006 point-mutant series. La P et al. 2006
8. E_q72_men1_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   IN CELLS EXPRESSING MENIN POINT MUTANTS (not a leukaemia system), point mutations in each of three menin nuclear localization signals - NLS1, NLS2 and a novel accessory NLSa - DO NOT BLOCK NUCLEAR TRANSLOCATION and DO NOT AFFECT MENIN'S ASSOCIATION WITH CHROMATIN, yet they ABOLISH menin binding to the IGFBP-2 promoter in vivo and compromise both repression of IGFBP-2 and induction of caspase 8. The authors read this as menin acting as a scaffold, with its NLSs controlling transcription rather than merely targeting menin into the nucleus.

   Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. · La P, Desmond A, Hou Z, Silva AC, Schnepp RW, Hua X · Oncogene 2006
   PMID 16449969DOI
   ▸What this evidence cannot show

   Abstract read in full; full text not read. NOT LEUKAEMIA, NOT HAEMATOPOIETIC, NOT KMT2A-REARRANGED (brief rule 73); the readout genes are IGFBP-2 and caspase 8 in an endocrine-tumour-biology context. THE DISTINCTION THIS SUPPORTS IS THE INTERESTING ONE AND ALSO THE FRAGILE ONE: bulk chromatin association (unchanged) versus locus-specific occupancy (abolished) are two different assays - a fractionation and a ChIP - and an assay-level difference can produce this pattern without a change in biology. It is NOT evidence that menin's chromatin binding is KMT2A-independent: KMT2A was not manipulated in this experiment at all.

   ▸Evidence that argues against this (1)

   • The one genome-scale measurement of where menin actually sits points away from reading any of this as a promoter-scale scaffold rule. Menin profiling in OCI-AML2 defines 3,423 menin-solo loci plus 1,733 shared with H2AK119ub, and this graph's own join onto that published locus list found MEN1 and KMT2A both H2AK119ub-ONLY - NEITHER NAMESAKE LOCUS IS MENIN-BOUND. A protein with occupancy that broad is poorly described by a model derived from two reporter genes. Zhou X et al. 2024
9. E_q72_men1_loc3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   IN MOUSE EMBRYONIC FIBROBLASTS AND TRANSFECTED CELLS (not leukaemia), menin is LOCALIZED TO CHROMATIN AND TO THE NUCLEAR MATRIX, and the NUCLEAR-MATRIX ASSOCIATION IS ENHANCED BY GAMMA-IRRADIATION, in the same paper that reports a menin-FANCD2 interaction enhanced by gamma-irradiation and increased DNA-damage sensitivity in menin-null MEFs. That sentence is the ENTIRE published subnuclear description of menin, and it is a biochemical fractionation rather than a compartment seen in a microscope.

   Menin associates with FANCD2, a protein involved in repair of DNA damage. · Jin S, Mao H, Schnepp RW, Sykes SM, Silva AC, D'Andrea AD, Hua X · Cancer Res 2003
   PMID 12874027
   ▸What this evidence cannot show

   Abstract read in full; full text not read. This citation is ALREADY LOAD-BEARING IN THIS GRAPH (cited in 6 entries; the localisation sentence is already written out inside interface-menin-fancd2 evidence E1) - brief rule 82 applies, so this entry cites rather than restates it, and the reader should go to interface-menin-fancd2 for the interaction claim, whose functional prediction was later tested and came back NEGATIVE (mech-men1-and-fancd2-act-in-distinct-crosslink-repair-processes). MOUSE FIBROBLASTS, not human, not haematopoietic, not KMT2A-rearranged (rule 73). 'Nuclear matrix' is an operational fraction defined by extraction conditions, contested as a structure, and not a compartment that can be pointed at in an image; a protein can appear in it because it is tightly bound to something that is, which for menin is exactly the expected confound. PubMed returns NO DOI for this record, so none is stored here.

   ▸Evidence that argues against this (1)

   • No independent replication exists, and the absence is bounded. On 2026-09-21, PubMed E-utilities esearch on menin[tiab] AND (subnuclear[tiab] OR nucleolus[tiab] OR 'nuclear body'[tiab] OR speckle*[tiab]) returned 6 records and NONE is about menin's own localisation: four NPM1c reviews naming menin only as a drug target, one NPM1c chromatin paper, and one diabetic-cardiomyopathy paper that matched on SPECKLE-TRACKING ECHOCARDIOGRAPHY - the same colliding namespace already logged in data/symbol-collisions.json under AF17. Zero in titles and abstracts; supporting figures not searched (brief rule 80). UniProt Consortium 2026
10. E_q72_men1_loc4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    IN ADULT KMT2A-REARRANGED AND NPM1-MUTANT AML CELLS AND IN PATIENTS ON THE REVUMENIB TRIAL, menin inhibition EVICTS MENIN AND MLL1 FROM CHROMATIN, and somatic MEN1 mutations at the revumenib-menin interface mediate clinical resistance precisely by PREVENTING that eviction. This is the only measurement of menin's own localisation under the drug this project is built around, and it is a CHROMATIN-OCCUPANCY readout - nobody has imaged where menin goes.

    MEN1 mutations mediate clinical resistance to menin inhibition. · Perner F, Stein EM, Wenge DV, Singh S, Kim J, Apazidis A, Rahnamoun H, Anand D, Marinaccio C, Hatton C, Wen Y, Stone RM, Schaller D, Mowla S, Xiao W, Gamlen HA, Stonestrom AJ, Persaud S, Ener E, Cutler JA · Nature 2023
    PMID 36922589DOI
    ▸What this evidence cannot show

    Abstract read in full; full text not read. ADULT AML, mixed KMT2A-rearranged and NPM1-mutant, NOT infant B-lineage KMT2A::AFF1 (brief rule 73). 'Eviction from chromatin' is occupancy loss and says NOTHING about which compartment menin occupies afterwards - soluble nucleoplasm, a nuclear body, the cytoplasm and destruction are all consistent with the same data. See localization-menin-inhibition-fusion-fate, which records the matching absence from the fusion's side. A resistance mutation preventing eviction is also consistent with reduced drug binding rather than with a distinct localisation mechanism. BOUND ADDED 2026-09-22, and the absence SURVIVES. 'Nobody has imaged where menin goes' was asserted without a bound. Measured: `menin[tiab] AND (immunofluorescence[tiab] OR imaging[tiab] OR microscopy[tiab]) AND (revumenib[tiab] OR "menin inhibitor"[tiab] OR MI-503[tiab] OR VTP-50469[tiab])` returns 1 record, and it was FETCHED: PMID 41588063, 'Menin-MLL inhibitors as a new therapeutic target for middle ear cholesteatoma' (Sci Rep 2026) -- an ear disease, not menin localisation imaging in leukaemia. Two breadth controls through the identical code path: `MEN1[tiab] AND (immunofluorescence[tiab] OR microscopy[tiab])` = 36 and `menin[tiab] AND "menin inhibitor"[tiab]` = 118, so neither operand is dead and the 1 is meaningful. Bounded to titles and abstracts; supporting figures not searched (rule 80), which matters here because an immunofluorescence panel is exactly the kind of result that lives in a supplementary figure.

    ▸Evidence that argues against this (1)

    • THE OCCUPANCY LOSS MAY NOT BE A RELOCALISATION AT ALL. Menin-MLL inhibitors reduce menin PROTEIN LEVELS and shorten menin's half-life in MLL-fusion leukaemia cells with no change in MEN1 mRNA, rescued by proteasome or E1 inhibition, through inhibitor-promoted menin-CHIP interaction and increased menin ubiquitination. If the drug degrades menin, then 'menin is evicted from chromatin' and 'there is less menin' are not separable by ChIP, and a localisation conclusion drawn from occupancy alone is confounded by abundance. Any experiment imaging menin's fate under a menin inhibitor must normalise to total menin protein in the same cells. Wu Y et al. 2019
11. E_q72_men1_loc5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UNIPROT'S RECORD FOR MENIN IS THINNER THAN THE LITERATURE AND CITES THE WRONG PAPER FOR IT. Fetched from UniProtKB on 2026-09-21, O00255 (MEN1_HUMAN, primary gene name MEN1, 610 aa) carries exactly ONE SUBCELLULAR LOCATION value - 'Nucleus' - with exactly one evidence attribution, ECO:0000269 to PMID 12874027, the menin-FANCD2 co-immunoprecipitation paper. The 1998 PNAS paper that established the nuclear localisation by three methods is NOT cited for the location. The feature table annotates NO nuclear-localization-signal motif on menin at all, although three have been mapped functionally, and it carries no subnuclear value of any kind - no nucleoplasm, no chromatin, no nuclear matrix - despite the cited paper itself reporting chromatin and nuclear-matrix fractions.

    UniProtKB entry O00255 (MEN1_HUMAN), SUBCELLULAR LOCATION comment and feature table · UniProt Consortium · UniProtKB 2026
    ▸What this evidence cannot show

    This is a database state on a date, not a biological finding, and UniProt curation changes. It is recorded because 299 gene entries in this graph take their stated compartment from this field (see ana-uniprot-localization-is-not-a-measurement-in-a-quarter-of-this-graph), and menin is the entry where the gap matters most. ECO:0000269 means 'experimental evidence used in manual assertion' - it certifies that a curator read an experiment, NOT that the cited paper is the founding or best experiment for the claim, and here it plainly is not. Nothing about the code is wrong; the inference 'the cited PMID is the localisation paper' is what fails.

    ▸Evidence that argues against this (1)

    • Do not over-read the absent NLS feature. UniProt annotates sequence-model NLS motifs sparingly, and the 2006 point-mutant series is itself a reason not to annotate one: if mutating NLS1, NLS2 and NLSa does not block import, a curator has a defensible reason to leave the motif out. The honest reading is that menin's import determinant is UNRESOLVED at residue level, not that the database missed something. La P et al. 2006
12. Q127_epi1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Menin activates transcription of the cyclin-dependent kinase inhibitors p27Kip1 (CDKN1B) and p18Ink4c (CDKN2C) by recruiting MLL to their promoters and coding regions; loss of function of either MLL or menin down-regulates both and deregulates cell growth.

    Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. · Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, Schnepp RW, Krankel C, Livolsi VA, Gibbs D, Hua X, Roeder RG, Meyerson M, Hess JL · Proc Natl Acad Sci U S A 2005
    PMID 15640349DOI
    ▸What this evidence cannot show

    Cell lines and transfection, not endocrine tissue; abstract read, full text not opened. ZERO mentions anywhere in this corpus before cycle 89, which is notable for the paper that supplies the molecular content of this entry's own endocrine-paradox section.

    ▸Evidence that argues against this (1)

    • A pharmacological menin inhibitor RAISED p27 while suppressing H3K4 methylation in osteosarcoma cells, which is the opposite of what this recruitment model predicts. Different tissue, tool compound, and a rise co-occurring with apoptosis - but it is one of only two pharmacological measurements of this axis and it does not agree with this one. Tian S et al. 2025
13. Q127_epi2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In vivo, expression of CDK inhibitors including p27 and p18 is disrupted in mouse islet tumours lacking menin; chromatin immunoprecipitation shows menin associates directly with regions of the p27 and p18 promoters and increases methylation of lysine 4 of histone H3 there; and that H3 Lys-4 methylation is reduced at both loci in islet tumours from Men1 mutant mice.

    Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. · Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK · Proc Natl Acad Sci U S A 2005
    PMID 16195383DOI
    ▸What this evidence cannot show

    Mouse ISLET TUMOURS rather than normal islets, so a reduced mark could be a consequence of transformation as well as a cause. The abstract says 'methylation of lysine 4 in histone H3' without resolving me1, me2 or me3, and 2005-era H3K4 antibodies do not cleanly discriminate them, so this entry deliberately does not write H3K4me3. Abstract read, full text not opened. ZERO mentions anywhere in this corpus before cycle 89.

    ▸Evidence that argues against this (1)

    • Measured in islet TUMOURS from Men1-mutant mice, so the reduced mark is confounded with transformation. The physiological arm - pregnancy lowering islet menin and beta cells proliferating, reversibly and without tumours - shows the same axis moving without any neoplastic outcome, which is the strongest argument that a partial, time-limited reduction of this mark is not by itself oncogenic. Karnik SK et al. 2007
14. Q127_epi3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Although Mll1 is required for the H3K4 methylation of only a SUBSET of Hox genes, menin - a component of both the Mll1 and Mll2 complexes - is required for the OVERWHELMING MAJORITY of H3K4 methylation at Hox loci, while loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect there.

    Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. · Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM, Ge K, Krumlauf R, Shilatifard A · Mol Cell Biol 2009
    PMID 19703992DOI
    ▸What this evidence cannot show

    Mouse embryonic fibroblasts, not a haematopoietic or endocrine cell and no fusion present. 'Overwhelming majority' is the authors' wording with no percentage in the abstract; abstract read, full text not opened, and the menin depletion method and its efficiency are therefore not recorded. That KMT2B carries the residual is an INFERENCE from 'a component of the Mll1 and Mll2 complexes', not a source claim - the paper as abstracted does not test MLL2 loss. ZERO mentions anywhere in this corpus before cycle 89.

    ▸Evidence that argues against this (1)

    • Mouse embryonic fibroblasts, and the haematopoietic study of the same question reaches a weaker conclusion: the Mll-dependent HSC network contains both menin-dependent AND menin-independent targets. If blood behaves like that rather than like the fibroblast Hox cluster, menin's chromatin footprint in the tissue this project cares about is smaller than this item implies. Artinger EL et al. 2013
15. Q127_celltype1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Men1 mRNA is expressed at a similar level in endocrine and non-endocrine mouse organs, whereas MLL, p27 and p18 mRNAs are predominantly expressed in endocrine organs, with pituitary p27 approximately 12-fold and MLL approximately 17-fold higher than liver; Men1 heterozygotes show no change in MLL, p27 or p18, while MLL heterozygotes show significant reductions in p27 mRNA and protein in pituitary and in p27 and p18 in pancreatic islets, but not in liver.

    Haploinsufficient and predominant expression of multiple endocrine neoplasia type 1 (MEN1)-related genes, MLL, p27Kip1 and p18Ink4C in endocrine organs. · Taguchi R, Yamada M, Horiguchi K, Tomaru T, Ozawa A, Shibusawa N, Hashimoto K, Okada S, Satoh T, Mori M · Biochem Biophys Res Commun 2011
    PMID 22037578DOI
    ▸What this evidence cannot show

    Mouse, mRNA by RT-PCR with protein shown only for pituitary p27; single paper, no replication identified; abstract read, full text not opened, so n per group and normalisation are unrecorded, and - importantly for this entry - whether PARATHYROID was in the panel cannot be determined from the abstract. The 12-fold and 17-fold figures are ratios against liver, an arbitrary reference. ZERO mentions anywhere in this corpus before cycle 89.

    ▸Evidence that argues against this (1)

    • Transcript is not dosage sensitivity, and this entry's own data record menin at about 6.8 nTPM in parathyroid, its joint-lowest tissue, in human. A mouse mRNA survey showing uniform Men1 across organs does not establish that menin protein is uniformly available, nor that a tissue with average transcript has average tolerance to partial inhibition. Human Protein Atlas consortium 2026
16. Q127_celltype2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    For MEN1 (ENSG00000133895) the Human Protein Atlas records RNA tissue specificity 'Low tissue specificity' with distribution 'Detected in all', blood cell specificity 'Low immune cell specificity' and blood lineage specificity 'Low lineage specificity'; single-cell RNA is 'Cell type enhanced' with megakaryocytes at 37.1 nCPM; the antibody-based tissue call is 'Group enriched' with bone marrow, lung and lymphoid tissue as top tissues, on a single antibody HPA030342 whose IH reliability is 'Uncertain'; subcellular main location Nucleoplasm with additional Cytosol.

    Human Protein Atlas - MEN1 (ENSG00000133895), machine-readable gene record · Human Protein Atlas consortium · proteinatlas.org 2026
    ▸What this evidence cannot show

    Fetched 2026-09-23 from the per-gene JSON endpoint, which does not return the HPA release version, so this row can drift silently. The protein-level call rests on ONE antibody with IH reliability explicitly 'Uncertain' - materially weaker than KMT2A's three-antibody 'Enhanced' record - and no tissue conclusion should be drawn from it. The megakaryocyte enhancement is the only cell-type-resolved human statement HPA makes about this gene and has no functional support anywhere in this corpus; it is recorded, not interpreted.

    ▸Evidence that argues against this (1)

    • HPA's protein-level tissue calls should be distrusted as a class, not just here. For KMT2A, three antibodies with 'Enhanced' IH reliability produce two mutually discordant calls - bone marrow and hepatocytes - so a single-antibody 'Uncertain' call for MEN1 carries even less weight than its own reliability label suggests. Human Protein Atlas consortium 2026
17. Q127_cellstate1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In primary human pancreatic beta cells the menin-MLL interaction inhibitor MI-2 together with TGF-beta signalling inhibitors synergistically increased ex vivo replication without affecting insulin production, and the cooperation was attributed to down-regulation of the cell-cycle inhibitors CDKN1A, CDKN1B and CDKN2C.

    Combined inhibition of menin-MLL interaction and TGF-beta signaling induces replication of human pancreatic beta cells. · Pahlavanneshan S, Behmanesh M, Oropeza D, Furuyama K, Tahamtani Y, Basiri M, Herrera PL, Baharvand H · Eur J Cell Biol 2020
    PMID 32646642DOI
    ▸What this evidence cannot show

    Ex vivo human donor islets over days; MI-2 is an early tool compound, weaker than MI-463/MI-503 and not a clinical molecule; transcript-level with NO chromatin readout, so it confirms the transcriptional direction and says nothing about H3K4 methylation. Abstract read, full text not opened. Already cited twice in this corpus (mechanism-menin-inhibition-replicates-human-beta-cells-ex-vivo, concept-menin-inhibition-is-an-active-therapeutic-hypothesis) and in neither case in this entry.

    ▸Evidence that argues against this (1)

    • OPPOSITE DIRECTION IN A NON-ENDOCRINE TISSUE. In osteosarcoma lines MI-503 markedly suppressed H3K4 methylation and INCREASED p27, alongside increased cleaved PARP. Two pharmacological measurements of this axis exist in the literature and they disagree in sign; neither measured H3K4 methylation at a CDK-inhibitor promoter. Tian S et al. 2025

• ← related toThe reversibility question: months of partial occupancy against a syndrome built from decades of loss

  2026-09-19: off-then-on Men1 systems exist (PMIDs 36552783, 17184987) and the onset side is bounded at ~10 weeks in mouse beta cells (PMID 28420716)

• ← related toTurn menin off for a defined window, then back on: the missing experiment that would bound reversibility

  existing restoration designs (PMIDs 36552783, 17184987) and the onset bound (PMID 28420716)

• ← depends onChidamide (tucidinostat) - the HDAC inhibitor in both of this graph's menin-inhibitor combination papers, and the only one paired with a menin inhibitor in the lymphoid index disease

  the combination's rationale requires the menin-MLL interaction inhibitor arm; menin resistance mutations would remove it

• ← related toHypothesis: menin inhibitors differ in how much JUND they liberate, and the least JUND-liberating compound will be the most durable

  feasibility objection: MLL1 and JUND peptides occupy the same deep central pocket in the same manner, so a pocket-occupying ligand has little structural room to spare one mandate

• ← analogous toAgency law — actual authority, apparent authority, and what revocation cannot undo

  menin mapped to an agent holding a revocable power of attorney

• ← analogous toFiduciary conflict of interest — law does not remove a conflicted agent, it separates the mandates

  menin as a fiduciary serving the leukemic, JUND and endocrine mandates from one office

• ← related toAnalysis (runnable): can a menin ligand tell KMT2A from JUND? A structural and co-folding selectivity profile of the whole inhibitor class

  profiles the menin pocket against all its deposited client complexes

• ← related toPICALM::MLLT10 (CALM-AF10), t(10;11)(p13;q14) - the DOT1L-dependent HOXA fusion that contains no KMT2A

  no menin-binding motif is present, and no study has tested menin dependence - counted absence as of 2026-09-20

• ← related toCALM-AF10 was meant to separate the menin axis from the HOXA programme - and the indirect evidence has now turned against separability, because KMT2A-free HOXA lesions keep proving menin-DEPENDENT

  predicts no menin requirement in a HOXA-high, KMT2A-wild-type fusion

• ← testsSort KMT2A-rearranged blasts by cell-cycle state, then measure menin-inhibitor response — the one-week experiment nobody has run

  target engagement readout on the menin-KMT2A axis

• ← depends onThe stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell

  menin is required for long-term HSC function under competitive stress and is co-recruited with the spreading fusion

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

  conditional menin loss preserves steady-state progenitors but causes a marked long-term HSC defect under competitive transplantation

• ← depends onCell 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

  MEN1 has the largest KMT2A-rearranged selectivity in the panel (-0.901) and moves only -0.168 when the fusion is held constant and cell type varies

• ← related toHypothesis (first clause REFUTED 2026-09-21): the fusion's core dependencies may be cell-type-invariant, but the cell type itself is not fixed

  MEN1 moves only -0.168 across the same-fusion cell-type contrast against -0.901 of KMT2A-r selectivity

• ← related toKMT2B has no haematopoietic cell-state result, and two of the seven records that look like one are about a different gene in muscle

  Mll1;Mll2-deficient murine MLL-AF9 cells are MORE sensitive to menin-interaction inhibitors

• ← related toTreating the five menin inhibitors as one drug, when a 2026 title says they are not

  the shared target whose inhibitors may not behave alike in infant ALL

• ← related toTrack the sub-1% cooperating-lesion clones through menin inhibition, because nobody has measured what the drug selects for

  MEN1 is on the panel deliberately, to separate on-target resistance from cooperating-lesion selection

• ← related toPrimary hyperparathyroidism in MEN1: the first and commonest consequence of losing menin

  germline MEN1 haploinsufficiency plus a somatic second hit in parathyroid chief cells

• ← related toPancreatic neuroendocrine tumours in MEN1: the manifestation that kills, and the one the animal data points at

  beta-cell Men1 ablation gives hyperplastic islets at 2 months and insulinoma at 6 months with full penetrance

• ← related toPituitary adenoma in MEN1: the third manifestation, and the one that matters most for a growing child

  third most frequent MEN1 manifestation; 32% of screened carriers, ~40% maximum age-related penetrance

• ← related toThe MEN1 age-penetrance curve: 7% by age 10, 52% by 20, 87% by 30

  what lifelong MEN1 haploinsufficiency produces per unit time

• ← related toBoth approved menin inhibitors cause multi-organ hyperplasia in animals, and one of them in the pancreas irreversibly

  loss of a tumour suppressor produces hyperplasia before it produces tumours

• ← bindsJUND - the AP-1 subunit menin holds down, and the one a menin inhibitor lets go

  JunD is the only Jun or Fos family member menin binds directly; menin represses JunD-activated transcription

• ← part ofMenin-JunD: the same pocket, the same drug, the opposite job

  one deep peptide-binding pocket serving two partners with opposite transcriptional outputs

• ← regulatesA 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

  XPO1 reported to stabilise menin on chromatin (preprint)

• ← related toAttribution 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

  menin-inhibitor pharmacodynamics are read from an anti-MLL-N track that contains wild-type MLL as well as the fusion

• ← related toSET / 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

  a second N-terminal contact would be a menin-inhibitor-independent route to HOXA; overlap with MBM1/MBM2 unknown

• regulates →H3K79me2 - the di-methyl state the leukaemia actually runs on, and the one menin turns out to govern only half of

  CRISPR-ChIP: menin required for the oncogenic, fusion-directed half of H3K79me2

• ← related toH3K79 methylation is what keeps Polycomb off - and that, not gene silencing, is what a DOT1L inhibitor actually undoes

  the two inhibitors converge on PRC1.1 by different routes

• ← related toEvery DOT1L dependency number this project has computed, in one place, lineage-split and in raw Chronos units

  MEN1-DOT1L co-dependency r 0.681 leukaemia-only, 95.4% retained after lineage adjustment

• ← depends onMenin inhibitors should leave half the H3K79 methylation standing - and if they do not, the menin-interface model is wrong somewhere

  menin is required for the fusion-directed H3K79 unit only

• regulates →MHC class I is a bivalent gene set, and a menin inhibitor derepresses it - shown in K-562, SCLC and neuroblastoma, and measured on HLA-A in primary AML, but never once in a KMT2A-rearranged cell

  indirectly - menin is not bound at bivalent MHC-I promoters; the effect is KMT2A redistribution

• binds →CIITA - the class II transactivator, a gene menin sits on, and the only antigen-presentation gene in this disease with a knockout that proves the drug acts through it

  menin occupancy at the CIITA and HLA-DR loci confirmed by ChIP-qPCR; contrast with no menin at bivalent class I promoters

• ← depends onThe platform argument's best evidence: one drug, two genotypes, one interface

  the shared obligate interface that makes the platform possible

• ← related toALL-PO (CVCL_1069) — an infant KMT2A::AFF1 line that is already in DepMap and has never been screened

  the one infant KMT2A::AFF1 line in DepMap with no MEN1 gene-effect value

• ← related toRS4;11 (CVCL_0093) — an ADULT KMT2A::AFF1 line, MSI-high, carrying NSD2 E1099K

  weakest MEN1 gene effect of the five KMT2A-rearranged lines checked (-0.463)

• ← related toHB11;19 (CVCL_8227) is KMT2A::MLLT1, not KMT2A::AFF1 — and it is the most menin-dependent line in the panel

  strongest MEN1 gene effect of the five lines checked, on a non-index partner

• ← related toBounded absence: no published CRISPR or dependency screen in any infant-derived KMT2A::AFF1 model

  no genome-scale loss-of-function data exists in infant index-fusion material

• ← co-occurs withDPY30 — the smallest COMPASS subunit, and the only one that behaves like a selective dependency

  leukemia co-dependency r=0.45 (54 DepMap lines, survives Holm)

• ← co-occurs withFLT3 / CD135 — the strongest non-tether co-dependency, and a target the field may have written off on a badly executed trial

  leukemia co-dependency r=0.65, 4th strongest and strongest outside the tether

• ← co-occurs withMEF2C — an output-program transcription factor, the second-strongest leukemia co-dependency, and a gene humans cannot spare one copy of

  leukemia co-dependency r=0.53; plausibly a lineage effect

• ← co-occurs withBCL2 — the one co-dependency in this beat that already has an approved drug pointed at it

  leukemia co-dependency r=0.43 (54 lines, survives Holm)

• ← related toCDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion

  both are parathyroid tumour suppressors that KMT2A-fusion leukemia nonetheless requires

• ← co-occurs withMEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

  leukemia co-dependency r=0.47, survives Holm; may track MEIS1 expression rather than shared process

• ← related toHCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind

  the two sides of the 2004 discrimination — menin binds fusion KMT2A, HCF-1 does not

• ← supportsFirst systematic enumeration of the KMT2A fusion interactome, and the diff against this graph

  menin is the only enumerated wild-type complex component shown to bind fusion KMT2A, and ranks 1st of 17,728 genes on KMT2A selectivity

• ← related toMenin is the best handle on KMT2A::AFF1 because of where the break falls, not because menin is biologically special

  reframes menin's primacy as a consequence of breakpoint position

• ← related toPCGF1 — the PRC1.1 scaffold whose LOSS causes menin-inhibitor resistance, so it is a restraint on the leukaemia rather than a dependency of it

  PRC1.1 and menin-KMT2A co-occupy bivalent noncanonical menin targets; menin inhibition phenocopies polycomb disruption

• ← related toPRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion

  PRC1.1 and menin-KMT2A co-occupy a bivalent class of promoters; menin inhibition phenocopies polycomb disruption

• ← bindsNPM1 (nucleophosmin) — the nucleolar shuttle whose mutant form binds chromatin with KMT2A and buys the second menin-inhibitor indication

  NPM1c binds chromatin targets co-occupied by KMT2A and confers menin dependence, which is the basis of the second approved menin-inhibitor indication.

• ← related toNSL complex - the MOF assembly that five NUP98 fusions bind alongside MLL1, and that competes with MLL/COMPASS for WDR5

  Supports the general menin-MLL1 thesis - a second fusion family converges on the same wild-type MLL1 node - while weakening the KMT2A-specific form of it.

• ← bindsMED12 - a named menin-associated protein that restrains menin's transcriptional output, and the anchor of the CDK8 module a KMT2A-r AML paper co-targets

  MED12 is named as a menin-associated protein alongside KMT2A, WAPL and GATA3 - but MAPs are reported to RESTRAIN menin's transcriptional function.

• ← related toMED23 — 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

  One of only three genes in this beat's 23-gene panel to survive the lineage split, alongside MEN1 and KMT2A.

• ← related toLineage-split dependency for the round 5 panel: 23 genes, 2 myeloid-identity artefacts caught, and 3 survivors of which one has no literature at all

  MEN1 at myeloid z -2.29 and B-lineage z -2.28 is the calibration for what a genuine lineage-independent dependency looks like.

• ← related toThe 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

  MEN1 is the positive control and outperforms every RNA-layer gene by roughly sevenfold

• ← related toThe RNA layer and the menin interface are separable: IGF2BP3 depletion sensitises MLL-AF4 leukaemia to menin inhibition and outperformed it alone

  Tests whether the menin interface is sufficient, by adding a post-transcriptional axis alongside it

• ← bindsMBM2, 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

  MBM2 binds the same menin cavity at 1,400 nM

• ← supportsFive new arginine-axis entries in one day, and not one of their genes is a selective dependency - in an instrument that recovers MEN1 at p=5e-05 and TDRD3 is not a dependency at all

  instrument validation: MEN1 -1.2629 in KMT2A-r vs -0.3745 other, diff -0.8885, p 5e-05

• ← related toThe CRM1 address is not a menin-free address: NPM1c reaches HOXA the same way and NPM1c AML is menin-inhibitor-sensitive in the clinic

  WHAT SEPARATES MENIN-DEPENDENT FROM MENIN-INDEPENDENT IS NOT THE ADDRESS, on this argument.

• ← related toRunning the HOXA programme is not enough to need menin

  Menin dependency dissociates from HOXA/MEIS1 programme membership across the two non-KMT2A lesions.

• ← supportsTwo of the three top new dependencies are myeloid identity, not KMT2A

  MEN1 is the only panel gene with an essentially zero lineage-split gap, which is what a dependency on the fusion rather than the cell should look like.

• ← supportsBRD9 survives the null; CEBPA sits at the median of random genes

  MEN1 falls at the 0.00th percentile on a statistic capped by its weaker lineage half.

• ← supportsThe easy null was not the problem, and nothing in 2,018 genes beat menin

  No gene in a 2,018-gene blind sweep scored more extreme than MEN1 on the lineage-consistency statistic.

• ← related toExactly one gene in 8,248 beats menin, and it is FLT3

  MEN1 sits at the 0.01st percentile of 8,248 genes, second only to FLT3 on this statistic.

• ← related toThe same pocket suppresses JUND: menin inhibition's unmeasured endocrine liability in infants

  menin's dual role: tumour suppressor in endocrine tissue, oncogenic cofactor in blood, through one shared peptide pocket

• ← bindsESR1 / estrogen receptor alpha - menin's best-documented non-leukaemic partner, and the only one a menin inhibitor is being given to patients to disrupt on purpose

  menin coactivates ERalpha hormone-dependently

• ← supportsIs the selectivity just pan-essentiality? No: it explains 0.4% of the variance

  MEN1's selective requirement survives adjustment for pan-essentiality: residual z = -12.2, the most extreme of 22 probes, despite MEN1 being only mildly essential on average (-0.363).

• ← supportsThe whole protein-coding genome: menin is still first, and a metabolic pathway appears (run)

  most selectively required gene in KMT2A-rearranged lines out of the entire protein-coding genome

• ← supportsThe assumption the whole project rests on, tested at last: menin dependency is fusion-specific (run)

  MEN1 is required 0.87 gene-effect units more in KMT2A-rearranged lines, beyond all 918 random genes tested

• ← regulatesHDGFL2 / HRP-2 - the second IBD protein, which binds KMT2A at the same site with the same affinity and does NOT need menin to do it

  menin overexpression raises LEDGF binding and lowers HRP-2

• ← testsRanking every KMT2A::AFF1 partner on dependency versus essentiality

  ranks every partner on required-by-the-cancer against needed-by-normal-tissue

• proposed by →Scott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug

  established menin dependency and drove the preclinical inhibitor work

• proposed by →Michael Cleary (Stanford) & Akihiko Yokoyama (National Cancer Center, Tsuruoka) — the groups that discovered the menin requirement itself

  identified menin as the oncogenic cofactor and LEDGF as its partner

• ← part ofMEN1 drug-interface mutations — the first proof that a chromatin drug can drive Darwinian escape in patients
• ← testsCo-dependency scan: what else does a menin-dependent cell need? (run, not planned)

  asks what else a menin-dependent cell needs

• ← testsDoes the menin co-dependency survive lineage adjustment? (run)
• ← analogous toFiduciary conflict of interest — law does not remove a conflicted agent, it separates the mandates

  menin as an agent serving two principals with conflicting interests

• ← supportsThe platform argument's best evidence: one drug, two genotypes, one interface

  one asset serving both KMT2A-rearranged and NPM1-mutant disease is the platform argument's best evidence

• ← refutesOf the menin co-dependencies, which are actually safe to hit? (run)

  menin is more human-constrained and more broadly required than LEDGF, its own adaptor

• ← related toTarget safety triage v2: constraint with its uncertainty attached (run)

  menin is AMBER on properly powered constraint (LOEUF 0.204 from 58 expected variants)

• ← supportsDepMap agrees with the mouse genetics: ARID1B is not a FUSION-SELECTIVE dependency (+0.0145, p=0.80) and reads -0.08 in both groups - but CYCLE 81 SHOWED THAT FLATNESS IS PARALOGUE BUFFERING, not dispensability. ARID1A and ARID2 ARE dependencies and are equally so in both groups - so no BAF subunit tested is fusion-selective. And MEN1 (-1.26) is a harder and more selective dependency than KMT2A itself (-0.81)

  unplanned control result: MEN1 is -1.2629 in KMT2A-rearranged lines against -0.3745 elsewhere (diff -0.8885, p=5e-5), a harder and more selective dependency than KMT2A itself

• ← related toRe-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

  MEN1 is 19/30 covered and its nine absent partners are all major cancer genes, dispatched as Q128

• ← related toDepMap co-dependency cannot rank the 97 unwritten interactome partners either, pan-cancer OR restricted to leukaemia lines: mean r 0.008 rising to 0.023 under restriction while the leukaemia-matched null rises with it, giving 1.08x the chance-expected count. Recomputing the null on the restricted lines is the only thing that stopped this being reported as a discovery, and my first pass criterion called a below-chance result a PASS

  MEN1's absent partners rank no better than chance; SMAD4 is the highest at r=0.069 pan-cancer

• ← related toNOT YET REPLICATED (corrected cycle 97). Within the K562 map KMT2A's 25-of-50 promiscuity is explained by size (97.1st percentile falling to 90.7th among proteins its own length) and menin is under-reached at the 23.5th, surviving an abundance control. The replication attempt was UNINFORMATIVE, not negative: eleven of twelve other proximity panels do not sample the nucleus, and the one that does shows the same shape

  menin is reached by 3 baits against a size-matched median of 6 - the 23.5th percentile, labelled LESS than its size predicts

• ← related toCORRECTED SAME CYCLE: the replication test was UNINFORMATIVE, not negative. Eleven of the twelve proximity panels do not sample the nucleus - they are centrosome, RTK, kinase, ion-channel, CFTR and mitochondrial baits - so KMT2A's 0th percentile in three of them measures panel composition, not promiscuity. In the one transcription-factor panel KMT2A is at the 71.7th and menin is absent, which is DIRECTIONALLY CONSISTENT with the K562 result at n=1

  menin is absent from eleven of twelve proximity publications and scoreable in one, where it sits at the 0th percentile

• ← related toGSE299100 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

  MEN1 ChIP under five different menin inhibitors in the index fusion, with matched inputs

• ← related toq172's four-line index arm is three KMT2A::AFF1 lines from TWO donors plus an ENL line; dropping the ENL line moves MEN1 7.7x more than DAXX, and menin's lost significance is variance, not effect

  menin remains the most REQUIRED of the four genes; it loses significance because the comparator strengthens

• ← related toMenin dependence varies 2.83x across KMT2A::AFF1 lines and the spread survives at three donors - but RS4;11 is last on KMT2A itself, so the heterogeneity is largely fusion-dependence heterogeneity, and DAXX is the one gene decoupled from it

  menin dependence tracks KMT2A dependence at Spearman +0.80 across four AFF1 lines, as a required cofactor should

• ← related toThe within-donor null: MEN1 sits at the 99.4th percentile of variation between two sublines of ONE child, and at the 98.9th between donors - menin dependence is not heterogeneous between patients so much as unstable in this background

  menin dependence moves 0.71 Chronos units between two cultures of one child's leukaemia - it cannot be used as a readout of interface strength

• ← related toAFF1 is NOT peptide-poor - it yields 49 detectable tryptic peptides against menin's 28, and menin cleared the identity threshold while AFF1 scored zero - but the two groups do not separate on peptide yield at all, so the driver is abundance

  menin yields 28 detectable peptides and clears the identity threshold; AFF1 yields 49 and scores zero

• binds →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)

  clamps the retained MBM1 motif, which is why partner identity does not matter to the drug

• ← supports49 of 91 proteins in this graph have never had a drug-like molecule bound to them

  MEN1 carries 45 distinct drug-like co-crystallised ligands with full construct coverage - among proteins retained in the fusion it is effectively the only one with a prosecuted medicinal-chemistry campaign.

• ← related toMenin residue numbers: the resistance literature (G331R) and the crystal structures (residue 326) disagree by exactly five

  numbering convention for the menin gene product

• ← related toMLL1 stays on condensed mitotic chromosomes and tethers menin there — a menin-dependent function absent from this graph until cycle 34

  A MENIN FUNCTION THIS GRAPH DID NOT CARRY: menin is tethered to condensed mitotic chromatin by MLL, and the paper reporting it was uncited here.

• ← bindsNUMA1 / NuMA (Q14980) - a nuclear-matrix protein that becomes the spindle pole, and the 5' partner of a variant APL fusion whose coiled-coil is required for oncogenicity

  same single atlas publication and method; three baits from one untargeted screen is one observation reported three times

• ← related toThe residue-type numbering check passed a site that is in the wrong place

  MEN1 S538 in the patient table is canonical S533; O00255-1 is not the canonical isoform

• ← related toNobody has ever run proximity labelling on a KMT2A fusion, and the interaction records that look like they did are RBP-atlas preys from HEK293

  ITS IntAct PROXIMITY ROWS ARE PREY DETECTIONS in a 50-RBP atlas in HEK293, not experiments on menin.

• ← related toMEN1 and CDK9 each carry exactly one genome-wide-significant in-gene common variant and PSIP1 two, so GWAS says almost nothing about on-target liability - yet the revumenib label lists hyperparathyroidism, the organ MEN1 loss famously affects

  near-empty GWAS locus; label hyperparathyroidism

• ← related toThe histone/ribosomal shape in the read queue is three classes, not one - H2BC21 is distinguishable AND essential at -0.70, so neither existing rejection ground reaches it, and HMGA1 is a harder dependency than MEN1 or KMT2A

  MEN1 -0.362 at 28.9% of 1,258 lines is a MILDER pan-panel dependency than HMGA1 -0.838 or H2BC21 -0.703; the entry flags that this comparison uses the wrong statistic for a selective dependency and must not be read as an argument against targeting menin

• ← supportsThe interactome instrument is migrated to IntAct REST: 277 partners, 118 written, 42.6% - the denominator grew by 60 and coverage fell 3.5 points, which is the instrument getting honest

  menin was the worst-served bait at 45.3%, and the rows the old endpoint dropped include the MI:0407 direct menin-KMT2A ITC record (PMID 22327296) - the most rigorous evidence class in this beat

• ← supports4,589 genes with no prior, and menin comes first (run)

  most selectively required gene in KMT2A-rearranged lines out of 4,589 scanned, and not pan-essential

• ← supportsSix of 85 proteins are both selectively required and drugged — and MEN1 is not close to the others

  Rank 1 with 45 distinct drug-like ligands; the only protein strong on both axes and not close to the others.

• ← related toWhere else in a child is the target switched on? (run)

  normal-tissue distribution of the target of the one approved drug in this disease

• binds →KMT2A / MLL1 — the gene that breaks

  menin clamps the KMT2A N-terminal MBM1 motif (Kd ~53 nM)

• ← part ofThe menin–KMT2A grip (MBM1), the interface the drugs actually block

  pocket in the menin TPR core

• ← inhibitsRevumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor

  target protein

• ← inhibitsZiftomenib (KO-539, Komzifti) — once-daily menin inhibitor approved in NPM1-mutant AML

  target protein

• related to →The fusion junction itself as a small-molecule target: a candid verdict

  the shared-pocket alternative to a fusion-selective surface

• ← related toNeither rival mechanism leaves its fingerprint, and the best correlate of Fanconi dependency is menin
• binds →KMT2B (MLL2/MLL4) - the other protein menin binds, and the one this graph never wrote

  menin recovered with MLL1 and MLL2 at equal stoichiometry and with neither SET1A/B nor MLL3/4 (quantitative AP-MS, HeLa)

• ← bindsMenin holds KMT2A and KMT2B, and the graph has been written as if it held one

  menin's KMT2 partnership is a two-member set: KMT2A and KMT2B, and neither KMT2C/D nor SETD1A/B

• ← related toJohnson & Johnson / Janssen — bleximenib (JNJ-75276617): paediatric from age 2, but not infants, and the dedicated child study was withdrawn

  Counter-evidence (Miao 2026, PMID 41849234): ziftomenib also retains activity against T349M and G331R with matching co-crystals, so escape of revumenib-resistance mutants is a class property rather than a bleximenib differentiator -- and M327I/G331D defeat more than one compound, implying a small shared breaking set at the interface

• ← related toJolanta Grembecka & Tomasz Cierpicki (University of Michigan) — the chemistry that made the menin interface druggable

  Counter-evidence: ziftomenib keeps the same binding pose against T349M and G331R yet loses potency, and is resistant to M327I/G331D -- pose preservation does not rescue the interface

• ← related toScott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug

  Counter-evidence (competing-interests statement, PMID 36922589): named inventor on menin-inhibition patent WO/2017/132398A1 plus an issued 'Menin inhibition in NPM1 AML' patent, with current research support from Syndax and Janssen -- the menin interface is encumbered IP for this collaboration

• ← refutesRob Pieters, Inge van der Sluis & the Interfant consortium (Princess Maxima Center, Utrecht) — the only global infant-ALL trial network

  Counter-evidence (NCT05327894): Interfant-21 is recruiting 160 infants with blinatumomab only and registers no menin inhibitor -- the sole global infant-ALL network is not testing the menin interface in the frontline

• ← supportsAnalysis: cross-validating the single-group non-menin KMT2A-fusion dependencies in one framework

  Counter-evidence that cuts for the thesis (Yan 2026, PMID 41501053): AKAP95 is reported as required for MLL-rearranged leukemogenesis yet dispensable for normal and regenerative haematopoiesis -- a menin-like profile, and it was not on the candidate list

• ← related toScott Armstrong & Andrei Krivtsov (Dana-Farber / Boston Children's) — the group that turned menin dependency into a drug

  generated the preclinical VTP-50469 package that established menin as a drug target and identified MEN1 interface mutations as the clinical resistance mechanism

• ← related toMichael Cleary (Stanford) & Akihiko Yokoyama (National Cancer Center, Tsuruoka) — the groups that discovered the menin requirement itself

  founding demonstration that menin is an essential oncogenic cofactor for MLL-associated leukemogenesis

• ← inhibitsJolanta Grembecka & Tomasz Cierpicki (University of Michigan) — the chemistry that made the menin interface druggable

  MI-2 and MI-2-2 (Kd 22 nM) bind the MLL pocket of menin and reverse MLL-fusion transformation

• ← related toPatricia Ernst (University of Colorado) — what normal KMT2A and menin actually do, which is the therapeutic-window question

  showed menin and MLL1 are genetically separable in normal haematopoiesis, the basis of the therapeutic window

• ← related toAnalysis: cross-validating the single-group non-menin KMT2A-fusion dependencies in one framework

  uses MEN1's selectivity profile (not common-essential, sharply depleted in KMT2A-r lines) as the positive-control benchmark

• ← depends onLEDGF occupancy under revumenib: the measurement the graph called missing exists, in one 2025 preprint, and it goes the way the tenfold cooperativity predicts

  menin occupancy is the cooperative term

• ← analogous toThe result that runs the wrong way: in Psip1-null cells Hoxa and Hoxd expression goes UP, because Psip1 also recruits Bmi1 and Ctbp1

  both clamp members are bivalent transcriptional cofactors

• ← related toYou can lower LEDGF without a LEDGF ligand: its protein half-life is about 4 hours against a proteome average of 20, so blocking guanine nucleotide or rRNA synthesis takes it out first

  menin protein falls alongside LEDGF under the same agents

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

  If CXXC does not supply the address, the menin-LEDGF tether and the pre-existing chromatin state are the remaining candidates — the decision-relevant test for the menin-interface hypothesis

• ← depends onThe nuclear pore and NUP98 fusions — a fusion that takes a pore protein's disordered repeats off the pore and builds nuclear droplets with them

  menin dependency in NUP98-r AML; inhibitor evicts the fusion protein itself

• ← related toWhere does the fusion go when menin inhibition evicts it? Almost nobody has looked - the published readouts are chromatin occupancy, the one protein whose fate was measured properly is menin, and the single human observation of fusion loss is confounded by a lineage switch

  menin itself is degraded via CHIP/Hsp70 under inhibitor; the fusion has not been tested

• ← confers resistance toAnalysis (runnable): is there a shared cell-state signature behind non-genetic menin-inhibitor and BET-inhibitor resistance?

  Counter-evidence (Perner 2023, PMID 36922589): the documented clinical resistance mechanism is a somatic MEN1 interface mutation, which a transcriptional or chromatin cell-state signature cannot detect.

• ← related toJUND - the AP-1 subunit menin holds down, and the one a menin inhibitor lets go

  Counter-evidence (Ma 2021, PMID 33821572): MI-503 and MI-463 abolish menin-JunD co-IP dose-dependently at 30-300 nM, and the in-vivo endocrine phenotype at 70 mg/kg/day for 12 weeks was compensatory beta-cell proliferation with IMPROVED glucose tolerance, not neoplasia. The entry's 'no co-IP under drug has been published' premise is withdrawn.

• ← related toHypothesis: the PTH rise on menin inhibitors is on-target and exposure-dependent, not renal

  Counter-evidence (Ma 2021, PMID 33821572): the endocrine tissue with a demonstrated in-vivo pharmacological menin-inhibition phenotype is the pancreatic islet, not the parathyroid, and at 12 weeks the effect was compensatory beta-cell proliferation with IMPROVED glucose tolerance. Prior probability lowered 0.35 -> 0.25.

• ← related toTurn menin off for a defined window, then back on: the missing experiment that would bound reversibility

  Counter-evidence (Ma 2021, PMID 33821572; Muhammad 2017, PMID 28270438): the 'cheap pharmacological arm to run first' has substantially been run - 12 weeks of menin inhibitor at 70 mg/kg/day gave increased beta-cell proliferation with improved glucose tolerance and no tumour - and tamoxifen-inducible Men1 deletion lines already exist. The drug does not reproduce the ablation phenotype at 12 weeks.

• ← related toPituitary adenoma in MEN1: the third manifestation, and the one that matters most for a growing child

  Counter-evidence (Biondi 2004, PMID 15060136; Gillam 2015, PMID 24531709): conditional Men1 loss leaves pituitary development normal and is NOT sufficient to initiate pituitary tumorigenesis; Men1(+/-) pituitary tumours require CDK4 and show LOH, both absent in Cdk4-null animals. Reversible pocket occupancy supplies neither.

• ← related toHR genes are menin-bound at 1.76x and so is ribosome biogenesis at 1.78x: the pathway-specific reading does not survive its own control

  A MENIN FUNCTION OUTSIDE THE KMT2A INTERFACE: occupancy over the homologous recombination machinery, converging with MEN1-loss HR deficiency in another disease.

• binds →FANCD2 — the FA effector menin binds, and the weakest FA gene in this graph's own selectivity scan

  one 2003 co-IP in MEFs; menin 214-390 sufficient; gamma-IR enhanced

• ← part ofMenin-FANCD2: one 2003 co-immunoprecipitation, a curated sufficient region of menin 214-390, and nothing since

  menin side of the interface

• ← related toThe menin-FANCD2 bridge is dead: it was tested in 2008, the mutation spectra differ, and there is no genetic interaction

  MEN1 has an ICL-repair role distinct from the Fanconi genes

• ← depends onFifth explanation for the Fanconi signal: it runs through menin binding FANCD2, not crosslink repair — tested, refuted, prior 0.07

  the hypothesis requires a functional menin-FANCD2 contact

• inhibits →RELA (p65) — menin binds it and represses it, and it is required to keep MLL oncoproteins on chromatin

  menin represses p65-mediated transactivation; menin 300-381 necessary

• binds →NFKB1 (p105/p50) — the only menin-NF-kB subunit with a co-immunoprecipitation, and the arm the MLL leukaemia data points at

  co-IP and pull-down, PMID 11526476

• binds →NFKB2 (p100/p52) — menin binds the non-canonical subunit too, and activating that arm SUPPRESSES MLL-AF9 leukaemia

  GST pull-down only, PMID 11526476

• ← part ofMenin represses NF-kB transactivation — through a mapped central region, a SIRT1 cofactor, and an RPA2 off-switch, in every tissue except the one this project cares about

  menin is the repressor

• binds →CSNK2A2 - CK2's other catalytic subunit, expressed in every KMT2A-rearranged line and, if anything, slightly favourable to lose

  tandem affinity purification co-elution in the Polycomb complexome map (PMID 27705803); the only menin-CK2 evidence that exists

• binds →HCFC2 — menin's other host cell factor, present in the founding paper by gel filtration and never mentioned again

  gel filtration co-elution in the founding 2004 paper; no co-IP

• binds →MYH9 (non-muscle myosin IIA) — the best-validated menin partner nobody in this field talks about, and the only one that maps to menin's N-terminus

  TAP-MS, GST pull-down, co-IP, actin selection; menin N-terminus to NMHC II-A head domain

• binds →EBF3 — a single large-scale MS hit against menin, in a B-lineage transcription factor family, which is the only reason it is worth recording

  single row in a 338-bait FLAG AP-MS screen

• ← related toTen of menin's 33 IntAct partners come from one BRET screen for MUTATION-created interactions — and five are gains caused by a named allele

  disposition of menin's curated IntAct partner list

• ← related toMenin's 33 curated partners, enumerated: 10 written, 10 discarded as mutation-directed or single-method, 3 that are not proteins, and what was read and rejected

  full ledger of menin's 33 curated partners and their disposition

• ← regulatesMenin is a brake the beta cell releases on purpose: pregnancy and glucose both lower it

  Menin restrains beta-cell proliferation and is itself down-regulated by pregnancy/prolactin and by glucose (Karnik 2007; Zhang 2012)

• ← regulatesMenin represses GLP1R - the receptor a whole class of diabetes drugs exists to switch on

  Menin, with PRMT5, represses GLP1R transcript and PKA-mediated FOXO1/CREB phosphorylation in beta cells

• ← regulatesMenin inhibition in the gut, not the islet: MI-463 raises GLP-1 from intestinal L cells

  Menin restrains beta-catenin/TCF7L2-driven Gcg transcription in intestinal enteroendocrine cells; a tissue outside the MEN1 tumour spectrum entirely

• ← part ofA second brake, unconnected to JunD: menin is a TEAD1 corepressor with VGLL4 in the beta cell

  MENIN acts as a TEAD1 corepressor with VGLL4, repressing FZD7 and CCN2 in beta cells

• ← inhibitsMenin inhibition makes adult human beta cells divide in a dish - the hardest thing in beta-cell biology

  MI-2 blocks the menin-MLL interaction; the resulting human beta-cell replication runs through down-regulation of CDKN1A, CDKN1B and CDKN2C - the same restraint whose loss drives Men1 neuroendocrine tumours

• ← related toThe menin-inhibitor plus PARP-inhibitor experiment is genuinely unrun, but its rationale should be DNA repair, not HOXA9 - and the evidence comes from a disease where menin is a tumour suppressor

  MENIN OUTSIDE THE INTERFACE: MEN1 loss impairs double-strand break repair via reduced BRCA2 in pancreatic neuroendocrine tumour, a function the KMT2A-interface framing does not cover.

• ← regulatesIMPDH2 - the rate-limiting guanine-nucleotide enzyme whose inhibition lowers LEDGF and menin protein and dismantles the MLL-fusion complex itself

  guanine-nucleotide supply sets menin protein abundance via rRNA transcription

• ← regulatesGuanine nucleotide supply sustains the LEDGF/menin/MLL-fusion complex - the one place in this graph where metabolism sits UPSTREAM of the menin interface

  guanine-nucleotide supply sets menin protein abundance

• ← bindsThe KMT2A::MLLT1 chimeric protein: exactly what survives the join on each side, in residue numbers

  menin-binding motif at KMT2A 6-25 is retained in every KMT2A::MLLT1 architecture

• ← depends onKOPN-8 (CVCL_1866): the field's default KMT2A::MLLT1 line, and its fusion protein has no YEATS domain

  MI-2 GI50 7.2 uM, lowest of four MLL-r lines in that panel

• ← depends onMenin dependence of KMT2A::MLLT1: real, repeatedly demonstrated, and always as one lane of a partner panel

  menin dependence of this partner, demonstrated genetically, chemically and in PDXs

• ← depends onMenin 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

  MLL-AF9 co-IP is the biochemical anchor of the class

• ← related toIKK inhibition and menin inhibition evict the fusion from chromatin by routes that do not share a node, so they should be additive — and the same reasoning predicts that a menin inhibitor alone partially defeats itself. Prior 0.30

  the second, non-overlapping route: menin is a direct tether, NF-kB is not

• ← supportsWhat is actually conserved across KMT2A partner classes — forced self-association, with two documented exceptions that break the rule

  the general mechanism implies a retained-N-terminus target, i.e. menin

• ← related toMenin dependence of a non-elongation KMT2A fusion has never been demonstrated — the counted absence, and what the pivotal trial actually enrolled

  the partner-independence claim and its untested boundary

• ← supportsHypothesis — the elongation hijack is how one partner class satisfies a more general requirement, and the general requirement is what should be drugged

  predicts menin is the partner-agnostic target the reframing privileges

• tests →SAVE (NCT05360160): the first prospective menin-inhibitor trial to report a NUP98-rearranged subgroup outcome

  the target whose inhibition the trial evaluates

• ← supportsThe first published complete remission of NUP98-rearranged AML on a menin inhibitor (icovamenib/BMF-219, n=1)

  grade 3 differentiation syndrome as on-target pharmacology in a NUP98 patient

• ← depends onWhy a nucleoporin fusion needs menin-MLL1: the second menin-dependent fusion family, and what it borrows rather than carries

  NUP98 fusions depend on endogenous menin-MLL1 although they contain no KMT2A sequence

• ← testsDepMap cannot answer whether MEN1 is selectively required in NUP98-rearranged lines, because it contains none — and it takes only ~3 to answer it

  MEN1 Cohen's d -1.879 in KMT2A-r vs other leukaemia; NUP98 arm empty

• ← refutesNUP98::KMT2A, inv(11)(p15q23) — the NUP98 fusion that contains KMT2A and is menin-inhibitor RESISTANT

  loses the menin-binding motif and is menin-inhibitor resistant

• ← proposed byMenin dependency tracks the availability of an intact menin-binding motif, in cis or in trans — not the fusion family

  cis or trans availability of the menin tether as the response variable

• ← refutesCOG AAML0531/1031 (n=2,080): MLLT10 fusions are adverse, and the 5-prime partner barely changes it

  PICALM::MLLT10 has no KMT2A N-terminus and no menin-binding motif yet matches KMT2A::MLLT10 outcome

• ← related toBounded absence: no menin-inhibitor trial reports response rate by 3-prime fusion partner in the primary literature

  the class claim for menin inhibition across partners rests on one sentence in the primary literature

• ← testsThe clinical outcome data do not support a single KMT2A class, and they do not refute the menin interface either

  whether the menin-KMT2A class abstraction is supported by clinical outcome data

• ← supportsThe CRISPR-ChIP H3K79 partition is a mouse MLL-AF9 result: resolved from GEO after the full text proved unreachable

  menin required for the fusion-directed H3K79 unit - in mouse MLL-AF9

• ← depends onImport class 5: evidence borrowed from fusions that are not KMT2A fusions at all

  the cross-family menin dependency that argues against fusion specificity

• ← refutesIn KMT2A::AFF1 there is no oncogenic DOT1L unit: all H3K79 methylation is the endogenous MLLT10-directed activity, working on genes the fusion has opened

  predicts menin inhibition should barely move H3K79me2 in t(4;11) cells

• ← depends onWhat could refute the menin-interface bet, restated after the provenance audit: three tests, none of which is about menin binding

  the interface whose evidence base is audited

• ← related toMLLT11 / AF1q — a 90-residue protein with no chromatin domain and no oligomerisation module, KMT2A partner in t(1;11)(q21;q23)

  menin dependence predicted from the retained KMT2A N-terminus but never tested for this fusion

• ← testsLineage-split DepMap: neither USP2 nor MAML2 is a dependency in KMT2A-rearranged lines, and USP22 is

  reference axis: MEN1 -2.29 / -2.28, the strongest lineage-independent dependency in the panel

• ← testsIs the menin interface a property of the fusion or of the blood? Test KMT2A::MAML2 thymoma

  asks whether the menin interface is intrinsic to the fusion protein or requires haematopoietic context

• ← related toMenin inhibitors are prescribed on 'KMT2A-rearranged', a category that contains proteins as different as KMT2A::AFF1 and KMT2A::USP2

  MBM1/MBM2 are retained by every KMT2A fusion in both BCRs, which is the counter-argument: the binding target is present regardless of partner

• ← related toPhase-2 dossier: the menin MBM1 pocket - the only candidate here that is already de-risked, and therefore the only one whose gate is clinical

  readiness layer on top of the menin biology entry

• ← regulatesPKA phosphorylates menin at Ser487 and pulls it off chromatin - a kinase input on the drug target itself

  PKA phosphorylation at S487 sequesters menin from chromatin

• ← regulatesDNA damage raises menin levels through ATM/ATR phosphorylation, and the residue has never been mapped

  DNA damage raises menin levels via ATM/ATR phosphorylation; residue unmapped

• ← related toA phosphosite on a menin target predicts who responds to a menin inhibitor

  a phosphosite on a menin-KMT2A target that gates response to menin inhibition

• ← related toWhen MYC falls after a menin inhibitor, there are three mechanisms it could be, and no published experiment separates them

  model B: menin binds the MYC transactivation domain directly and coactivates at E-boxes, independent of H3K4me3

• regulates →EZH2 - the Polycomb enzyme that collaborates with the fusion instead of opposing it, and that no single-agent inhibitor can switch off

  menin binds the Ezh2 promoter and promotes its expression (MLL-AF9)

• ← related toTrithorax against Polycomb at HOXA: the textbook antagonism, and the two ways this disease breaks it

  two published routes from menin inhibition to de-repression, with opposite predictions for PRC2

• ← depends onPRC2 is the fusion's repressive arm, recruited through menin, and the index disease's version of it runs to HDAC7

  menin is the licensing step; the hypothesis fails if EZH2 does not fall after menin inhibition

• ← co-occurs withAFF1-NPM1 proximity: nucleophosmin is the only bait in any published proximity experiment whose neighbourhood contains AFF1, KMT2A and menin together

  menin co-recovered in the same neighbourhood; 3 of 50 baits reach MEN1 at all

• ← related toWild-type KMT2A is one of the most promiscuously labelled proteins in the proximity record - 25 of 50 baits - and menin is one of the least, at 3

  menin recovered by 3 of 50 baits, all of which also reach KMT2A

• ← inhibitsHitting the same axis at two points was predicted to be sub-additive; the one published test found synergy in all four KMT2A-rearranged lines

  MI-463, tool menin inhibitor arm of the combination

• ← related toArginine methylation gates KMT2-complex access to chromatin at two residues, in both directions, independently of the menin tether AND of the WIN motif - a parallel control point, not a rival to menin dependence

  PARALLEL control point, NOT counter-evidence to menin dependence: menin plus CXXC sets where the fusion goes, the arginine gate sets whether a KMT2 complex can act on the tail once there

• ← co-occurs withAFG2A / SPATA5 (Q8NB90) - a 55LCC replisome-proteostasis ATPase that co-purifies with KMT2A and menin, and whose CURRENT symbol cannot retrieve its own source paper or any of its function literature

  same single HeLa S3 TAP (PMID 38554706); AFG2A bait, menin prey; MI-score 0.35

• ← related toThe interactome coverage figure is computed on 651 of the 1,015 IntAct rows available - 64% - and the gap is worst for menin and LEDGF, the two baits the menin-interface hypothesis rests on

  WORST-SERVED BAIT: PSICQUIC returns 62 rows for O00255 against 137 from IntAct REST (45%), and rule 93 established that the missing rows include the seven MI:0407 direct menin-KMT2A records

• regulates →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

  menin inhibition causes loss of ATF4 and the ATF4-dependent signature in MLL-rearranged B-ALL and in Ewing sarcoma, by transcriptional AND post-transcriptional mechanisms (PMID 33741715)

• ← refutesThe ATF4/ISR collapse under menin inhibitors reports loss of the KMT2A-fusion transcriptional programme by ANY route, not engagement of the menin interface - and the loss is of ATF4 activity, not ATF4

  refutes menin-interface specificity for this programme, while leaving the menin-dependent HOX/MEIS/MEF2C arm - which discriminates the two compounds by 1.0-3.8 log2 - intact

• ← depends onPHGDH (O43175) - the largest menin-SELECTIVE fall in the whole serine panel, and the least essential gene in it

  menin inhibition drops PHGDH -3.24 log2 in RS4;11 d7; H3K4me3 at the PHGDH promoter is menin-dependent in Ewing sarcoma

• ← related toThe 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

  menin-selective component of the serine arm; H3K4me3 at the PHGDH promoter is the published chromatin-level route

• ← depends onALDH1L2 (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

  transcript falls 3.40 log2 under VTP-50469; the menin-minus-DOT1L margin is line-discordant (-0.49 in RS4;11, -1.89 in MV4;11) and is not asserted

• ← depends onCBS (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

  largest fall in the panel (-4.07) with the second-largest menin-selective margin (-1.47); no chromatin measurement at the locus in any system

• ← depends onGPT2 (Q8TD30) - the EARLIEST-moving and third-most menin-selective gene in the serine arm, and the one REH cannot control because it is below the array floor there

  third-largest menin-selective margin in the panel (-1.03, only 33% reproduced by EPZ5676) and the earliest kinetics

• ← depends onThe serine/one-carbon programme has a SECOND, chromatin-proximal menin input that is not ATF4 - which is why PHGDH is menin-selective where CHAC1 is not, and why the arm is absent in KMT2A::MLLT3

  the second input proposed is menin-dependent and chromatin-proximal, by analogy with H3K4me3 at the PHGDH promoter in Ewing sarcoma

• binds →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

  menin SvID (aa 360-445), a surface distinct from the MLL-binding central cavity; patient mutants D418N and W436R lose binding

• ← related toThe residual fraction this graph says is absent from the entire literature, measured: FLAG-MLLAF9 enrichment at its own top 1,228 sites falls from 15.9x the genome median to 3.0x under VTP50469 - about 18% residual - and 12.8% of those sites stay in the top 0.1%

  the perturbation is pharmacological disruption of the menin-KMT2A interface

• ← related toMenin inhibition removes the fusion from its strongest sites without relocating it to a new programme, and PRC1.1 fills in only where the eviction is complete - so the drug's chromatin action is subtraction plus local substitution, not redistribution

  the perturbation is disruption of the menin-KMT2A interface

• ← related toIn 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

  the measurement is of menin occupancy: 14.91x to 1.96x enrichment, 10.58% of its own top 0.1% of bins retained

• ← related toAt the same bins in the same cells, menin's share ratio is 0.20-0.26 and the MLL1 N-terminus antibody's is 0.80-0.91 - so a shared-epitope MLL1-N ChIP under-reports the menin inhibitor's occupancy effect by 3.5 to 4.0-fold, and the number is now measured rather than asserted

  the comparator arm is anti-Menin (Bethyl A300-105A Lot 8) in the same chromatin

• ← related toUnder VTP-50469 in RS4;11, the 209 bins that rise to the top of the MENIN distribution are 3.7-fold CpG-island-enriched over a class-matched null at p = 5.2e-07, while the MLL1-N gained set is not enriched at all - so menin's residue is island-biased and an MLL1-N gain is not

  the survivors of menin eviction are 3.71-fold CpG-island-enriched over a class-matched null, and outrank menin's own real sites in the treated track

• ← related toIn 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

  menin is the component the drug is proposed to subtract

• ← related toAt 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

  menin is 0.2005 at the co-occupied set, the reference point the other three are read against

• ← related toThe 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

  menin's own share at its own top 0.1% of MOLM13 bins falls to 0.1602 under VTP-50469, the positive control for the whole arm

• ← related toThe shared-epitope masking calibration, run against a FLAG tag and then refuted by its own control: the MLL1 antibody reports 2.23-fold more retained signal than the tag at the fusion's own sites, but MLL1-dominated non-fusion sites fall HARDER than the fusion does (0.1069 against 0.1793), so no mixture of fusion and wild-type MLL1 can produce the observed 0.3995

  wild-type-dominated MLL1 sites lose share harder under a menin inhibitor (0.1069) than the tagged fusion's own sites do (0.1793), which is an on-target effect on wild-type menin-KMT2A complexes

• ← related toIn the only system where the fusion can be measured separately, a menin inhibitor removes MLL1 from wild-type-dominated sites harder than it removes the tagged fusion from its own sites - 0.1069 against 0.1793 - which is an on-target effect on normal KMT2A-menin complexes and an argument about toxicity nobody in this project has made from occupancy data

  menin recruits wild-type KMT2A/KMT2B as well as the fusion, and inhibiting it removes MLL1 from wild-type-dominated sites at least as thoroughly (0.1069 against 0.1793)

• ← related toZMYND11::MBTD1 is the KMT2A-fusion architecture assembled from different parts - and the part it throws away is a direct physical brake on KMT2A itself

  the absent adaptor - the disanalogy that matters most to this laboratory, since no protein is hostage in this fusion

• ← depends onZMYND11::MBTD1 AML is menin-inhibitor sensitive despite having no KMT2A rearrangement, because the translocation deletes ZMYND11's MYND domain and with it a physical brake on wild-type KMT2A

  the prediction is only about menin if MEN1 ablation phenocopies the drug; falsifier 4 makes that an explicit arm

• regulates →Menin's other address list: the same complex that switches on HOXA in blood writes H3K4 methylation onto the CDK inhibitors p27 and p18 in endocrine cells

  menin recruits MLL to CDKN1B and CDKN2C and raises H3K4 methylation there (PMIDs 15640349, 16195383)

• regulates →At the Hox cluster, menin is required for most of the H3K4 methylation and MLL1 is required for only a subset - the cofactor has a bigger chromatin footprint than the enzyme

  menin is required for the overwhelming majority of H3K4 methylation at Hox loci (PMID 19703992)

• regulates →Menin is dispensable for blood at rest and required for blood under stress - and that is a cell state, not a hedge

  menin is required for long-term HSC function under competition and recovery, not at steady state (PMID 19228930)

• related to →The tissue selectivity of MEN1 syndrome is not in MEN1: menin is expressed evenly everywhere and MLL, p27 and p18 are the endocrine-predominant ones

  menin mRNA is uniform across organs; MLL, p27 and p18 are endocrine-predominant (PMID 22037578)

• ← related toAbsence: the tissue with the clinical signal is the one tissue nobody has put under a menin inhibitor and measured - one record in the whole literature, and it is a review

  the untested tissue behind gene-men1's labelled hyperparathyroidism signal

• ← related toMeasured: the cell-type, cell-state and epigenetics literature for KMT2A and MEN1 was NOT missing from this corpus - 7 of 16 load-bearing papers were already cited, one of them 32 times, and 0 of 16 were in gene-kmt2a

  1 of 16 load-bearing sources was in this entry before cycle 89, and it was the positive control

• regulates →The endocrine cell's resting state is an actively maintained G1 restraint, and menin is what maintains it

  menin maintains the endocrine cell's reversible G1 restraint through CDKN1B and CDKN2C

• ← related toAll nine unwritten MEN1 partners trace to exactly two publications, neither of which mentions menin outside an antibody catalogue row

  adjudicates nine IntAct-curated MEN1 partners; 0 of 9 admitted

• ← related toMEN1-BRAF V600E: four methods and an endogenous menin lane - the only one of the nine that is a real observation, and it is still a property of the allele

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (c)

• ← related toMEN1-AKT1 is ONE BRET well from a mutation screen, for the E17K allele only - declined

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a, b and c)

• ← related toMEN1-EGFR is ONE BRET well from the extended-driver arm of a mutation screen, for L858R only - declined

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a, b and c)

• ← related toMEN1-PTEN is ONE BRET well from the extended-driver arm, for R173C only - declined

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a, b and c)

• ← related toMEN1-FBXW7 is four alleles of ONE BRET assay, all typed 'mutation with no effect' - declined, and it is the most insidious class

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a, b and c)

• ← related toMEN1-SMAD4 is four alleles of ONE BRET assay, all 'mutation with no effect' - declined, and the real menin-TGF-beta literature is elsewhere

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a, b and c)

• ← related toMEN1-SPOP is four alleles of ONE BRET assay, all 'mutation with no effect' - declined, with a nuclear-speckle confound

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a, b and c)

• ← related toMEN1-CD226 is two proteome-scale AP-MS maps, both spoke-expanded, both in cell lines that do not express CD226 - declined

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (b)

• ← related toMEN1-ZC3HC1 is one spoke-expanded BioPlex row in HCT116, and UniProt records ZC3HC1 weakly or not expressed in leukocytes - declined

  IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a and b)

• ← related toThree of menin's nine declined partners are E3 ligase substrate receptors - either menin turnover is ubiquitin-controlled, or substrate receptors are this beat's artefact signature

  proposes that menin abundance may be ubiquitin-controlled, which would set inhibitor occupancy

• ← related toIs menin an SCF-FBXW7 substrate? A one-week immunoblot and a free desk scan that settle Arm A

  measures menin protein abundance as a function of ubiquitin pathway status

• ← related toNo menin interaction outside the chromatin complex has ever been tested in a haematopoietic cell - 0 of 9, and the compartment is the wrong one in every case

  zero of menin's nine non-chromatin IntAct partners has been tested in a haematopoietic cell

• ← depends onIn 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

  the eviction is produced by inhibiting the menin-KMT2A interaction

• ← related toSGC0946 removes 86% of H3K79me2's share at the fusion's own sites and the four eviction quartiles are 0.1396 / 0.1453 / 0.1452 / 0.1360 - span 0.0036, Spearman +0.400, a bootstrap interval spanning zero - so a very large effect on this mark can carry no eviction-depth structure whatever

  the contrast that separates menin inhibition from DOT1L inhibition on this readout

• ← depends onIn MOLM13, human KMT2A::MLLT3, from the VTP-50469 founding paper's own series GSE127507, H3K79me2's aggregate response at MLL1-N's top sites is 0.998 - and the same sites split by eviction depth run 0.7746 / 1.0601 / 1.0995 / 1.1421 at Spearman -1.000, with the INPUT stratified identically staying flat

  MENIN occupancy as the second eviction stratifier

• ← related toIn human MOLM13, DOT1L's own occupancy under a menin inhibitor runs 0.1364 / 0.3083 / 0.3555 / 0.3913 across MLL1-N eviction-depth quartiles at Spearman -1.000 - the writer is lost in proportion to eviction depth, and its mark follows with a 2.9-fold smaller span

  the eviction is produced by menin-KMT2A inhibition

• ← depends onA menin inhibitor's chromatin signature is organised by how much fusion it removed from each site, so every mark's response is a GRADIENT in eviction depth - and any readout that averages over a fusion-occupancy set is underpowered by construction, sometimes to exactly 1.000

  the gradient is produced by menin-KMT2A inhibition

• ← related toPrey recovery in the two BioID depositions tracks SIZE and not abundance - and the interactome tail was being scored on the wrong side of the pair, because every one of the 22 partners is the BAIT and every core protein is the PREY

  menin is recovered by 3 of 50 RBP baits, half its predicted rate and the 30th percentile of its matched peers - hard to reach by proximity labelling

• ← testsFirst 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

  MEN1 ChIP occupancy at 15 canonical target loci under four drugs, MOLM13 4 d

• ← related toIn the same deposit, the MENIN inhibitor removes DOT1L from all five DMSO DOT1L peaks at canonical target loci (p = 0.0432) while all three DOT1L inhibitors keep 5/5 - and the VTP DOT1L library still calls ACTB, GAPDH and EEF1A1, which is the internal positive control the MEN1 arm lacks

  the menin inhibitor, not the DOT1L inhibitors, is what removes DOT1L from these loci

• ← related toResolving cycle 83's threat: the MLL1 channel moves under both drug classes and is therefore not diagnostic, but the MEN1 channel separates them completely - so 'menin displacement' remains a specific readout of menin-interface engagement and the corpus must stop treating the two channels as one

  menin displacement at pre-specified target loci is a drug-class-specific readout

• ← inhibitsVTP-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

  menin-KMT2A (MBM1) protein-protein interface inhibitor

• ← related toA 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.

  the partner whose patient-derived interface mutations are the control TK216 never had

• ← testsMenin does NOT leave chromatin when the fusion is removed: three hours after MLL::AF9 is degraded to 2.5-7.1% of its own chromatin sites, menin still holds 80.0% of its strongest peak calls genome-wide - so menin occupancy is not a readout of fusion occupancy, and a menin inhibitor that displaces menin is doing something fusion loss does not do

  MENIN RESIDENCE DOES NOT REQUIRE THE FUSION AT 3 h, GENOME-WIDE: 80.0% of menin's strongest peak calls survive fusion degradation, in cells where the fusion's own tag is at 2.5-7.1%.

• ← related toGSE173599 deposits menin ChIP at three hours and nowhere else - no 24 h, no 4 d - so the central question this beat raises, whether menin's persistence is fusion-independence or merely a slow off-rate, cannot be answered from the only degron deposit that exists, and the GEO record advertises four-day menin ChIP that was never deposited

  Bounded data-availability statement for menin under a fusion degron: 3 h only in GSE173599's deposited peak tables, despite the series overall_design describing four-day menin ChIP that was never deposited.

• ← related toThe HSPC-like blast fraction is the compartment that survives menin inhibition, and its size at diagnosis predicts depth and durability of response

  the drug target whose inhibition the compartment is hypothesised to survive

• ← depends onIn 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%)

  Site classes are defined by menin occupancy over a matched IgG control

• ← related toBounded absence: in GSE159608's SEM line, VTP-50469 was profiled for H3K4me3 only - no menin, no H3K27ac, no H3K79me2, no RNAP2 and no IgG under the drug - and no library in the series carries a spike-in normalisation, so an absolute change in any mark is unmeasurable here

  Menin CUT&Tag exists in SEM but was never crossed with the menin-inhibitor arm

• ← supportsIn 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

  Both KMT2A N-terminal libraries have menin as their nearest neighbour genome-wide in SEM

• ← related toIn SEM, H3K4me3 responds to menin displacement the way a partially redundant mark should: selectively at menin-bound sites, by about a quarter, and not at all under a DOT1L inhibitor - which bounds how much of a menin inhibitor's lethality H3K4me3 can be carrying

  The mechanism concerns displacement of menin from the KMT2A interface

• ← testsExperiment: a 6 / 24 / 72 hour / 7 day VTP-50469 time course in SEM reading menin occupancy and H3K4me3 together, to decide whether the 23% is a partial effect or a slow one

  Reads menin occupancy on the same axis as the mark, which no existing dataset does in this line

• ← related toMenin loses half its promoter signal where the fusion sat, and nothing where it did not

  menin loses 49.7% of promoter signal at fusion-occupied genes and 2.6% elsewhere, 3 h after fusion degradation

• ← related toA menin peak that keeps its call has still lost a sixth of its enrichment - and only where the fusion was

  menin sites that keep a peak call have still lost a sixth of their enrichment, but only where the fusion was

• ← related toThe menin inhibitor removes three-quarters of the fusion from its own promoters, replicated in two batches

  blocking the menin-MLL1 interface removes 73-75% of the fusion from its own promoters at 4 d, in two independent batches

• ← related toThe DOT1L inhibitor removes menin from fusion promoters too, which a pure interface model does not predict

  menin occupancy at fusion promoters is not diagnostic of the menin-KMT2A interface being broken

• ← related toFour days after the fusion is destroyed, menin signal at non-fusion promoters is 27% higher than control

  menin signal at non-fusion promoters is 27% above control 4 d after fusion degradation - redistribution or renormalisation, indistinguishable here

• ← related toMenin's departure is partial where the fusion's loss is total, so the two are not stoichiometrically coupled

  menin moves about half as far as the fusion does at the fusion's own promoters; the coupling is not stoichiometric

• ← related toHalf the menin at fusion-occupied promoters is held by a tether that is not the fusion

  proposes two menin pools at fusion target promoters, one fusion-dependent and one not

• ← related toGSE252378 contains menin CUT&RUN in exactly one patient - a KMT2A::ENL lineage-switching pair under a menin inhibitor - and none in any of its eight KMT2A::AFF1 patients

  no menin track in any KMT2A::AFF1 sample of the deposit

• ← related toThe 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

  constrains what the menin interface can determine

• ← related toThe compound in the only infant menin-inhibitor occupancy sample is revumenib, named in the abstract - and neither the dose nor the duration of exposure is recorded in the paper, the GEO record or the authors' repository

  revumenib occupies the menin pocket that binds the KMT2A MBM motifs

• ← related toNeither infant sample has an IgG control, and neither of their two sequencing batches contains one - so every number from this pair is confounded with chromatin accessibility

  the menin channel is the one most exposed to the accessibility confound

• ← bindsIn drug-naive primary infant KMT2A::MLLT1 B-ALL, menin is as enriched as the fusion N-terminus at the top fusion promoters (2.73x vs 3.12x over an accessibility reference) while the wild-type C-terminal reporter sits at background (1.10x)

  menin occupies the top fusion-N promoters at 2.73x accessibility-corrected enrichment in primary infant KMT2A::MLLT1

• ← related toMenin 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's retention at fusion peaks relative to the fusion's

• ← related toThe authors' own deposited table puts menin at 0.87 of its diagnostic-sample signal over their oncoprotein-target peaks, in the sample their text describes as having menin reduced to undetectable levels - the two statements are about different denominators, and only one of them travels

  the quantity in dispute is menin's chromatin retention

• ← inhibitsA 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

  a menin inhibitor occupies the menin pocket that binds the KMT2A MBM motifs

• ← bindsIn a patient, the menin-fusion association is demonstrable before the drug and unmeasurable after it - and the asymmetry is what this pair establishes, not a rate of menin loss

  menin tracks the fusion-containing N-terminal channel in primary infant material

• ← related toThe 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 compartment proposition is about menin

• ← related toSpike-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

  the primary readout

• ← related toAn occupancy readout returned background in every channel of the only drug-exposed patient sample it has been tried in - so a negative from such an assay cannot currently be told apart from an assay failure

  menin occupancy as an endpoint

• ← related toIndependent positive control: of 27 samples, the ONE that calls zero oncoprotein-target promoters is 152985 - the AML that arose during menin-inhibitor treatment, which the paper reports as having oncoprotein and menin reduced to undetectable levels

  menin also reduced to undetectable in the same aliquot, per the paper

• ← related toThe 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 interface is invariant while the occupancy amount is not

• ← related toIRX1 — Iroquois homeobox 1, the gene that names the HOXA-negative half of infant t(4;11) ALL

  IRX1 binds the MLL-AF4 complex WITHOUT changing bound menin

• ← supportsIRX1 binds the MLL-AF4 complex non-competitively — menin, LEDGF and DOT1L are all unchanged

  menin is UNCHANGED in the fusion complex when IRX1 binds - non-competitive

• ← related toIRX1 is a second address for the KMT2A::AFF1 oncoprotein, not merely the gene that turns HOXA off

  under this hypothesis the menin interface should still operate, at a different address

• ← testsMenin CUT&RUN in an IRX1-high KMT2A::AFF1 blast — the missing track in every public deposit

  menin genomic occupancy in the HOXA-negative subgroup - measured nowhere public

• ← related toIf the target promoter set is no more conserved within a patient than between patients, then nothing in the oncoprotein complex remembers the first disease

  the menin interface is identical in both states and does not predict the target set

• ← depends onHOXA occupancy is the partner-invariant: occupied in 17 of 18 non-AFF1 KMT2A-r samples, 2.94x to 29.1x
• ← related toUnder revumenib the oncoprotein leaves chromatin globally, so 'does IRX1 become a menin-inhibitor escape route' cannot be answered from this deposit
• ← related toSwap the AFF1 C-terminus onto a KMT2A-AF9 backbone and score IRX1 occupancy: the direct test of partner causality
• ← related toThe IRX1 address requires the AFF1 partner; the menin interface explains the shared HOXA address and not this one
• ← bindsMEN1-PIAS4 - DECLINED. The single supporting publication is a PARP-1 heat-shock sumoylation study in which menin is never named, and the row is a HeLa co-IP passenger

  single HeLa co-IP, menin prey in a PIASy pull-down; DECLINED

• ← related toThe 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

  MEN1 stops discriminating KMT2A-r from non-KMT2A once the comparator is restricted to B-lineage ALL (p 0.103), where DAXX does not

• ← analogous toIn pancreatic neuroendocrine tumours MEN1 and DAXX/ATRX are the two commonest mutations of the same tumour - and both are LOST there while leukaemia needs both intact

  MEN1 is the top mutated tumour suppressor in panNET and the required chromatin anchor in KMT2A-r leukaemia - the same gene with an inverted sign

• ← related toDAXX and ATRX as drug targets: six ChEMBL rows and zero of them an affinity, against menin's 1,776 - but three crystal structures of the interface that would have to be blocked

  scale comparator: menin carries 1,776 activity rows and the menin-MLL PPI 48,291, against DAXX's 6

• binds →RPA2 (RPA32) - the middle subunit of replication protein A, whose disordered N-terminus is the phospho-switch of the replication-stress response and whose 43-171 region binds menin

  menin aa 1-40 plus 286-448 to RPA2 aa 43-171; H139D/A160P/A176P abolish it

• ← part ofMenin binds RPA2 directly, the contact maps to RPA2 aa 43-171 across its low-affinity ssDNA site, and three MEN1 patient missense mutations abolish it - a 2003 finding that this graph had never cited despite menin being its central node

  interface entry for menin's RPA2 contact

• ← depends onThe menin arm and the CTCF arm are not two stories: menin/SETD2/H3K36me3/LEDGF licenses CtIP short-range resection and CTCF/H3K9me/HP1-gamma licenses BRCA1/BARD1-EXO1/DNA2 long-range resection, which are the two consecutive halves of ONE reaction - so a menin inhibitor and an H3K9-axis inhibitor are acting on the same pathway at different steps

  menin binds gammaH2A.X through Val371-Gln400, which is NOT the MBM cavity a menin inhibitor occupies

• ← related toNobody has reported what a menin inhibitor does to CXCR4: zero papers name menin and CXCR4 together, and the RNA-seq that would answer it is already public

  zero papers name menin and CXCR4 together in title or abstract

• ← part ofThe menin-gamma-H2A.X motif, menin Val371-Gln400: necessary, sufficient as a peptide, and the nine residues at its centre have never been seen in any of the 69 menin structures

  menin residues 371-400, the gamma-H2A.X recognition motif

• ← part ofThe SvID, menin 360-445: a truncation boundary the field reads as a domain, whose functional residues D418 and W436 are 10-20 A from every menin drug - but whose first ten residues ARE the drug pocket

  menin 360-445, the truncation-mapped SUV39H1 interaction window

• ← part ofThe menin acidic shelf, Glu366-Asp370-Val371: the counter-charge that MBM2 binds, resolved in 3U88 after all - and the one patch where the drug pocket, the SvID and the gamma-H2A.X motif all touch

  menin 363-378, the acidic shelf at the rim of the MBM cavity

• ← part ofMenin's nucleosome grip (8GPN): a three-patch surface at menin 353-362, 428-442 and 556-587 that holds H3, H4 and H2B - and touches H2A at exactly one residue

  menin 353-362, 428-442 and 556-587, the nucleosome-contacting face

• ← part ofThe menin side of the LEDGF clamp: residues 91-105 and 209-212, on the opposite face of menin from the drug pocket and 26-38 A from every other surface in this beat

  menin 91-105 and 209-212, the LEDGF IBD contact

• ← part ofMenin's two nuclear localisation signals, 479-497 and 588-608: mapped in 1998, verified residue-for-residue today, annotated by UniProt nowhere - NLS-1 in no structure at all, NLS-2 resolved in one

  menin NLS-1 479-497 and NLS-2 588-608

• ← part ofMenin-SETD2, mapped to the NTD and Palm and tooled with a peptide at menin 231-248: the third partner assigned to the same half of menin, and the writer arm of the HR scaffold

  menin NTD + Palm; Pep242 tool window 231-248

• ← related toADJUDICATION: the SvID and the gamma-H2A.X motif are OVERLAPPING BUT NOT THE SAME SURFACE - and the premise that made the question urgent, that the SvID is distinct from the MLL cavity, is FALSE at the SvID's own boundary

  a residue-level surface map of menin, which gene-men1 currently lacks (data.domains is null)

• ← related toA residue axis for menin, derived from coordinates: three spatial lobes, not four named ones, and the sharpest seam in the protein runs through the drug pocket

  supplies the structural residue axis gene-men1's data.domains explicitly says it does not have

• ← part ofThe menin small-molecule pocket as a coordinated surface: four clinical-stage compounds, 21-26 contact residues each, and bleximenib sitting on a different part of it from the other three

  the small-molecule pocket as a coordinated surface of menin

• ← related toMenin stimulates homology-directed repair through Chk1 and the region required is 1-228: a 2010 paper that is cited in no entry of this graph and in no reference list of the 2026 paper that reports the same conclusion

  menin stimulates homology-directed repair; the region claimed is 1-228

• ← related toMenin has never been tested against SET::NUP214 - a bounded absence in three independent registers: literature, cell-line dependency data, and the founding paper's own blots

  MEN1 mean DepMap Chronos gene effect -0.36 and not flagged essential, against a 22.8% CR+CRh rate for revumenib in centrally confirmed KMT2Ar - the register does not see the dependency

• ← testsHypothesis: SET::NUP214 activates HOXA partly through recruited wild-type MLL1, which would make a KMT2A-unrearranged leukaemia menin-inhibitor-sensitive

  the discriminating experiment: blot menin on an MLL1 immunoprecipitate from LOUCY with and without SET-NUP214 knockdown - recruitment and displacement predict opposite signs

• ← related toNUP214 / CAN - the cytoplasmic-face nucleoporin that CRM1 docks against, and the 3' partner of four leukaemia fusions

  the MEN1 value in this entry's own DepMap list (-0.36, not essential) is the demonstration that a pooled Chronos mean cannot see this graph's central dependency

• ← related toA 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

  menin coming off chromatin under an XPO1 inhibitor is equally consistent with the general effect of detaching an abundant chromatin cofactor (PMID 38917791 shows XPO1 loss detaches p300 across hundreds of loci); the preprint reports no non-menin chromatin factor as a specificity control

• related to →Where does the fusion go when menin inhibition evicts it? Almost nobody has looked - the published readouts are chromatin occupancy, the one protein whose fate was measured properly is menin, and the single human observation of fusion loss is confounded by a lineage switch

  menin is evicted from chromatin under revumenib but its compartment has never been imaged

• related to →Nuclear matrix and mitotic chromosome scaffold — KMT2A sits with topoisomerase II, in the same place the gene breaks

  menin fractionates with chromatin and the nuclear matrix, and the matrix pool rises after gamma-irradiation

• related to →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 only subnuclear readout menin has ever been measured on is the chromatin-versus-soluble axis

• related to →Menin-FANCD2: one 2003 co-immunoprecipitation, a curated sufficient region of menin 214-390, and nothing since

  menin chromatin and nuclear-matrix localisation comes from the same 2003 paper as the FANCD2 interaction

• expressed in →Th17 cell - the mature CD4 T-helper subset whose differentiation and maintenance require MENIN, which makes it the clearest published on-target normal-tissue liability of the menin interface

  RESIDENCY: in differentiating Th17 cells Menin binds the Il17a locus directly and is required there for permissive histone modifications and Pol II complex recruitment; it also binds the Rorc locus. Chromatin occupancy in the cell is the basis for this edge

• regulates →Th17 cell - the mature CD4 T-helper subset whose differentiation and maintenance require MENIN, which makes it the clearest published on-target normal-tissue liability of the menin interface

  REQUIREMENT, separate from the residency edge: Menin-deficient T cells do not efficiently differentiate into Th17 while Th1 and Th2 remain intact in vitro, and Menin is required to MAINTAIN Rorc expression in differentiated Th17 cells

• ← bindsRPRM (reprimo) - the other half of menin's Ewing 2007 pair, a protein with no experimental localisation at all, and a promoter methylated in 45% of paediatric AML

  single anti-bait co-IP row from Ewing 2007 (MEN1 as FLAG bait, HEK293, not spoke-expanded, observed in one experiment)

• ← related toZero of eight unwritten AFF4/MEN1 partners has an experimentally coded nuclear localisation, and the two that are called nuclear are called it by inference

  positive control: MEN1 returns ECO:0000269 Nucleus

• ← part ofMenin has no subnuclear compartment, and nobody has looked - the whole published record is two biochemical fractionations, both DNA-damage papers, and no microscopy at all

  Menin's subnuclear record as a bounded, dated, counted absence: two fractionations, no microscopy, nothing in a leukaemic cell

• ← related toEvery IntAct number in this project is drawn through a query that misses half the record - and what it misses is the taspase1 fragments

  menin's direct-interaction record with KMT2A is filed as isoform O00255-2 and is invisible to id:O00255

• ← related toMenin is the best-observed of the six core proteins and the only one whose interval separates from the rest - the interface the programme is built on is the one the record actually supports

  46.7% spoke-only against 71.9-78.6% for the other five; eight partners with an MI:0407 direct-interaction record

• ← related toWhat a curated interaction row actually claims: spoke expansion, and the ladder from 'was in the same tube' to 'touches'

  why the distinction matters here: the menin pocket argument is a direct-contact claim, and a spoke-expanded row cannot support one

• recruits →RBBP8 / CtIP - the only unwritten core-complex partner with a DIRECT-interaction record, and the graph already held its mechanism without holding the protein

  indirectly, via SETD2 -> H3K36me3 -> LEDGF (PMID 42578372, 2026)

• ← part ofMenin is a corepressor of the LXR sterol sensors - one paper supplies three of this graph's twelve missing partners, and the function has never been written down here

  a menin function outside chromatin, endocrine neoplasia and leukaemia - the first in this graph

• ← bindsNR1H3 / LXR-alpha - the best-observed of the three MEN1 sterol partners, with both directions curated in two species, and menin as its corepressor

  menin is a corepressor; 5 IntAct rows, 4 non-spoke, both directions curated in mouse

• inhibits →NR1H3 / LXR-alpha - the best-observed of the three MEN1 sterol partners, with both directions curated in two species, and menin as its corepressor

  menin represses LXR-alpha transcriptional activity in HepG2 and mouse liver

• ← bindsNR1H2 / LXR-beta - the paralogue arm of the menin-LXR contact, present in both species and absent from the paper's conclusion

  2 non-spoke co-IP rows, human and mouse, supplementary figure 4 only

• ← bindsSREBF1 / SREBP-1 - the weakest of the three MEN1 sterol partners, because it is simultaneously the pathway's readout

  one non-spoke co-IP, supplementary figure 6; role ambiguous - SREBF1 is also the pathway readout

• ← bindsFOXM1 - a one-panel MEN1 co-IP from a 4,119-row atlas, attached to a protein that is independently a validated MLL-rearranged leukaemia stem-cell dependency

  one non-spoke pull-down row, supplementary figure 3a of a 4,119-row TF atlas, miscore 0.4, never discussed

• ← depends onAR / 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

  Malik 2015 (PMID 25822367) places the AR-MLL-complex contact on the MENIN-MLL subunit and shows a menin-MLL inhibitor blocks AR signalling and CRPC growth; the Grasso co-IP panel this graph cites for AR-KMT2A contains no menin lane

• ← supportsThe 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)

  Menin occupancy is the variable that selects the fusion's 20% out of the uCpG pool: r2 = 0.96 with MLL(N) at fusion peaks, against 0.27 for CFP1.

• ← testsPut 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

  Menin ChIP is the decisive secondary readout: is 5mC gain random over the uCpG pool, or concentrated at menin-bound promoters?

• ← related toThe comparison that founded 'the CXXC contact is too weak' puts a 300 mM NaCl protein-DNA measurement against a 50 mM NaCl protein-peptide measurement

  Bears on every entry quoting the 53 nM menin-MBM1 affinity, none of which states the buffer.

• ← supportsRe-founding the address argument: the CXXC domain cannot specify a location at any affinity, and a tighter one would be worse

  Re-founds the menin-interface hypothesis's address argument on measured specificity and occupancy rather than on a Kd magnitude.

• ← supportsThe 41 residues after the CXXC fold (1204-1244) carry a substantial part of the fusion's DNA grip, and removing them is why the structural literature's affinity is so low

  If the basic tail carries sequence-independent affinity while the CXXC fold carries the specificity, affinity and specificity live in different pieces of the domain, which is what the menin-interface hypothesis requires.

• ← related toThe pivotal menin-inhibitor paper reports that the drug does NOT globally displace MLL1 or the fusion from chromatin - menin goes, the fusion largely stays

  menin is globally displaced in the same experiment in which the fusion is not

• ← related toEviction is a claim about menin. The field, and this graph, transfer it to the fusion without a measurement that supports the transfer

  the protein the eviction claim is actually about

• ← related toKerry 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

  corrects what Kerry 2017 establishes about menin's role in fusion recruitment

• ← depends onA chromatin-occupancy readout has one dimension and the question has three: eviction, degradation and relocation all lower the signal at a target gene

  menin's own degradation under the drug is the documented instance of the confound

• ← depends onOnly a handful of loci lose fusion occupancy under a menin inhibitor, and they are the same few whether menin is drugged or deleted: MEIS1, MEF2C, JMJD1C - not HOXA, not MYB

  the same short list is produced by pharmacological and genetic menin removal

• ← bindsSON (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

  SON interacts with menin and inhibits MLL complex assembly (wild-type MLL, PMID 26990989)

• ← related toSUMO1 - not a complex partner of LEDGF but a modifier of it, and the interactome row cannot tell you which

  The nearest SUMO-to-KMT2A-complex contact is SENP3 deSUMOylating RBBP5 in menin-containing MLL1/MLL2 complexes at HOX genes (PMID 24930734) - a WRAD-side switch, on the side of the breakpoint the fusion does not retain (Q91 2026-09-22)

• ← related toWhich KMT2A exon carries which interface: exon 1 is the menin-binding motif, exons 5-6 are the CXXC zinc finger (computed, not recalled)

  locates the menin-binding motif (aa 6-25) in KMT2A exon 1, the exon sarcoma fusions discard

• ← refutesYAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away

  the dominant fusion species contains no menin-binding motif, so menin cannot be recruited to it

• ← refutesVIM::KMT2A - the one KMT2A rearrangement that keeps the SET domain and still throws away the menin-binding exon

  menin-binding motif (aa 6-25) lies in the discarded KMT2A exon 1

• ← related toYAP1 (P46937) - the Hippo pathway's transcriptional co-activator, and a KMT2A fusion partner from a completely different functional class

  wild-type menin up-regulates Yap1 transcription in hepatocellular carcinoma - a different tissue, different direction, no fusion

• ← refutesIn leukaemia KMT2A gives the front of the protein; in sarcoma it gives the back. Every consequence follows from that.

  KMT2A rearrangement does not entail a menin interface; polarity decides it

• ← related toNobody has ever asked whether a KMT2A-rearranged sarcoma needs menin: zero records, and the reason is that no model exists

  the untested question: is menin required where its binding motif is absent from the fusion

• ← refutesThe 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

  menin dependence is not entailed by KMT2A rearrangement; it follows the 5-prime architecture

• ← related toThe predictable clinical error this beat exists to prevent: a menin inhibitor given for a KMT2A-rearranged sarcoma because of the gene name

  menin shows suppressor behaviour in MEN1-syndrome sarcomas, so the pharmacological direction may be wrong in mesenchyme

• ← related toBUD13 - a RES-complex splicing factor 1.66 Mb from KMT2A on 11q23.3, whose one chromatin paper puts it in the soluble fraction

  same single BUD13-bait record recovered MEN1 - the only queue row putting KMT2A and menin in one experiment, in a leukaemia line

• ← confers resistance toAFF1::KMT2A (AF4-MLL), the der(4) product: what it is made of, residue by residue

  Lacks the menin-binding motif (KMT2A 6-25) entirely, so it is outside the reach of any menin-interface inhibitor.

• ← confers resistance toAbout one KMT2A-rearranged patient in twenty has no direct fusion at all - only the reciprocal one

  No menin-binding motif is present in these patients at all, because the allele carrying it is absent.

• ← related toIn the only cohort that measured it, HOXA genes are ON in exactly the reciprocal-positive patients and OFF in the rest

  Challenges HOXA as a clean pharmacodynamic proxy for menin-dependent fusion activity in t(4;11).

• ← confers resistance toKMT2A*: a menin-blind, LEDGF-blind, SET-competent KMT2A protein made from out-of-frame reciprocal alleles

  Reported to have no ability to bind menin, because the binding motif is N-terminal and absent.

• ← related toThe MLL3/4-UTX switch fails to throw — menin inhibition kills by turning something ON, and cells that cannot turn it on survive

  MLL1-menin impedes MLL3/4-UTX at a subset of promoters; the drug removes that impediment

• ← related toSwitching menin inhibitors: four substitutions defeat all of them, three defeat only some, and the map now exists

  shared substitutions M327I/V/T and G331D; inhibitor-specific C334R, E368K/V, V372A

• ← related toSET::NUP214 is KMT2A-free in its sequence but not in its mechanism: it binds and condenses wild-type MLL1, which reopens the menin question this beat was sent to close

  if the recruited MLL1 is load-bearing, menin is on the SET::NUP214 HOXA programme - untested

• regulates →The KMT2A-fusion causal chain: six links, one measured ordering, and two arms that are parallel rather than sequential

  link 2: required for initiation and maintenance, not the determinant of oncogenicity

• ← regulatesNecessary is not explanatory: four different questions that a knockout answers as if they were one

  menin is the worked example of a requirement read as a determinant

• ← related toHypothesis: where a KMT2A fusion sits in the nucleus is set entirely by retained KMT2A modules, and no partner changes the compartment - so every published 'the fusion is here' result is a wild-type KMT2A result

  if the address is entirely N-terminal, menin is part of the address rather than downstream of it

• ← related toThe third category: modules lost from the fusion protein but supplied in trans by the wild-type KMT2A allele

  menin recruits both the fusion and the wild-type protein to the same HOX loci

• ← related toAuditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails

  the tumour-suppressor-therefore-do-not-inhibit inference has now been tested against this protein in 94 patients (AUGMENT-101, CR+CRh 22.8%)

• ← depends onMenin inhibition reported to induce CLEC12A and sensitise KMT2A-r and NPM1-mutant AML to CLEC12A-directed CAR cells (2026 preprint, not peer reviewed)

  the mechanism requires an intact menin-inhibitor response, which is what MEN1 resistance mutations remove

• ← related toSMARCA4 (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

  only curated interaction rows are null-effect BRET from one mutation screen; NOT a menin partner

• ← related toBAF does not work where the fusion works: most direct MLL-AF9 targets do not respond to Brg1 loss, and the SWI/SNF address is a distal MYC enhancer cluster 1.7 Mb away

  non-redundant with the menin axis: MYC via distal enhancers versus HOXA9/MEIS1

• ← related toBAF inhibition against the menin axis: on the evidence it is a complement, not an alternative - and the case rests on one laboratory

  the comparator axis; rank 1 against SMARCA4's 16,333 in the same scan

• ← related toKDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR

  KDM4C inhibitor SD70 synergises with the menin inhibitor MI-503 in MLL::AF9 AML

• ← related toAuditing the seven strikes before applying them: nine of ten decisions stand, four for different reasons than were given, and one clinical argument fails

  menin is the consistency test: any safety rule that would disqualify a germline tumour suppressor disqualifies the project's approved lead target

• ← related toIn 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
• ← related toCycle 102 declared before it ran that an input pair 'bounds library and coverage variation but NOT ChIP efficiency' and is therefore a LOWER BOUND - the size of that underestimate is now measured in human KMT2A::AFF1 MV4;11 and it is sixteen-fold at the peaks: 0.6% for an input pair against 9.4% for a menin ChIP pair over the same bins, in the same cells, on the same day
• ← related toAgainst a correctly measured same-condition floor, a menin inhibitor's effect on H3K4me3, H3K79me2 and H3K27me3 is a genome-wide redistribution - up in the decile below the peaks, down monotonically to the sparsest decile - while its effect on the FUSION stays confined to the top 0.1%. The drug displaces the complex at the peaks and moves the marks everywhere
• ← part ofMEN1 drug-interface mutations — the first proof that a chromatin drug can drive Darwinian escape in patients

  somatic mutations in the MEN1 coding sequence at the inhibitor interface

• ← inhibitsRevumenib (SNDX-5613, Revuforj) — first approved menin–KMT2A interface inhibitor

  disrupts the menin-KMT2A interaction

• related to →BET bromodomain inhibition in KMT2A-rearranged leukemia — spectacular preclinically, stalled clinically

  the essentiality contrast that defines the project's target-selection logic: MEN1 is not common-essential, BRD4 is

• ← inhibitsM-808 — a covalent menin-MLL inhibitor with a co-crystal, five years before the graph noticed it
• ← related toGraft-versus-leukaemia in KMT2A-rearranged infant leukaemia - the mechanism the whole transplant rests on, demonstrated in ALL generally, assumed in this disease, and with a published mechanistic reason to doubt it

  menin-KMT2A binding occupies genes encoding negative regulators of T-cell activation; inhibition reduces donor T-cell exhaustion

• ← related toThree unnamed things at once: the DOT1L-PRC1.1 deposition names the fusion, the cell types and both inhibitors with concentrations

  the deposition pairs DOT1L inhibition with VTP-50469 menin inhibition at 300 nM

• ← related toKMT2A-rearranged or NPM1-mutant? Both, in separate arms: WT-MA9 mouse, MOLM13, OCI-AML3, and two patients on AUGMENT-101

  MI-503, VTP-50469 and SNDX-5613 arms across mouse and human myeloid systems

• ← related toBounded failure: the founding menin-cofactor paper names no fusion, has no PMC record and deposited nothing - and three entries depend on it

  the founding menin-cofactor citation, unreadable by every free route

• ← related toMenin-bound genes are the RNA-processing and DNA-repair machinery, H2AK119ub-only genes are neuronal and developmental, and 'menin target' is therefore a much weaker label than this graph treats it as

  WHAT MENIN OCCUPANCY ACTUALLY MARKS OUT in this dataset: constitutive nuclear machinery, not a lineage or leukaemia programme.

• ← related toHalf the PRC1.1 intersection was free all along: Zhou's locus set is a publisher supplementary table, and 159 of this graph's gene entries are in it

  MEN1 IS NOT MENIN-BOUND HERE: it lands in the H2AK119ub-only group, which bounds how much any group label claims.