{"gene":"KMT2A","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1992,"finding":"KMT2A (HRX/ALL-1/MLL) was identified as a human homolog of Drosophila trithorax, encoding a predicted 431 kDa protein with AT-hook DNA-binding motifs (related to HMG proteins) and zinc finger domains; 11q23 translocations disrupt the HRX gene between these two motifs, generating chimeric fusion transcripts (e.g., HRX-ENL) from both derivative chromosomes, implicating KMT2A in multilineage leukemia through DNA binding at AT-rich sites.","method":"Molecular cloning, Southern/Northern blotting, sequence analysis, cell line characterization","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — original discovery with multiple orthogonal methods, highly cited foundational paper","pmids":["1423624"],"is_preprint":false},{"year":1992,"finding":"The t(4;11) translocation fuses ALL-1 (KMT2A) on chromosome 11q23 to the AF-4 gene on chromosome 4, creating reciprocal chimeric proteins; the ALL-1 gene spans ~100 kb with at least 21 exons, and the breakpoint cluster region spans 8 kb, consistently producing in-frame fusion oncoproteins.","method":"Molecular cloning, Southern blotting, Northern blotting, sequence analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — foundational cloning paper with multiple methods, independently replicated","pmids":["1423625"],"is_preprint":false},{"year":1991,"finding":"The MLL gene was identified spanning the breakpoint in 11q23 translocations [t(4;11), t(6;11), t(9;11), t(11;19)] associated with acute leukemias, establishing KMT2A as the recurrent target of these rearrangements.","method":"YAC clone mapping, molecular cloning, transcription unit identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — original locus identification, replicated across multiple translocations","pmids":["1720549"],"is_preprint":false},{"year":1993,"finding":"HRX rearrangements occur in at least nine distinct partner loci across diverse 11q23 abnormalities in de novo and therapy-related leukemias; all breakpoints localize to an 8-kb region encompassing exons 5–11 of HRX, indicating that fusion proteins consistently retain similar N-terminal HRX sequences.","method":"Southern blot analysis across 35 leukemia cases","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — large case series with consistent molecular mapping across multiple partner genes","pmids":["8389614"],"is_preprint":false},{"year":1993,"finding":"The t(4;11) translocation creates an HRX-FEL fusion where 913 C-terminal amino acids of FEL (AF-4), a basic, serine/proline-rich protein containing GTP-binding and nuclear localization sequences, are fused in-frame to the N-terminal DNA-binding portion of HRX, generating a chimeric transcription factor.","method":"cDNA cloning, sequence analysis, Northern blotting","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — direct molecular characterization of fusion protein structure","pmids":["8443374"],"is_preprint":false},{"year":1997,"finding":"HRX (KMT2A) protein is widely expressed in human tissues with punctate nuclear distribution, localizing to discrete nuclear structures/bodies in both normal and leukemic cells; chimeric HRX fusion proteins (HRX-ENL, HRX-FEL) retain nuclear localization with sizes corresponding to predicted fusion protein molecular weights.","method":"Immunocytochemistry with polyclonal/monoclonal antibodies, Western blotting of cell lines with t(11;19) and t(4;11) translocations","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — direct protein localization with validated antibodies across multiple cell lines and tissues","pmids":["9129043"],"is_preprint":false},{"year":1997,"finding":"Retroviral transduction of HRX-ENL into hematopoietic stem-cell-enriched populations dramatically enhanced myeloid colony formation, enabled serial replating (≥3 generations), established immortalized myelomonocytic cell lines, and induced myeloid leukemias in syngeneic and SCID recipients; the ENL component was required since a deletion mutant lacking ENL had no transforming activity, demonstrating gain-of-function leukemogenic activity of the HRX-ENL fusion.","method":"Retroviral gene transfer, in vitro colony replating assays, suspension culture immortalization, syngeneic/SCID mouse leukemia transplantation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays in vitro and in vivo with deletion mutant controls, highly cited","pmids":["9250666"],"is_preprint":false},{"year":1997,"finding":"The HRX/ALL1-eps15 fusion protein (from t(1;11)) localizes exclusively to the nucleus in smaller, more numerous nuclear bodies compared to wild-type HRX/ALL1 (which localizes to both cytoplasm and nucleus with larger nuclear bodies), indicating that fusion with eps15 alters subcellular compartmentalization of HRX/ALL1 as a potential activation mechanism.","method":"Immunofluorescence microscopy in transfected cells and leukemia blasts","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization experiment comparing wild-type vs. fusion protein, single lab","pmids":["9041173"],"is_preprint":false},{"year":1999,"finding":"Wild-type HRX and leukemic HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) directly interact with the GADD34 protein (confirmed by yeast two-hybrid and co-immunoprecipitation in human cells); coexpression of HRX fusion proteins abrogated GADD34-induced apoptosis following ionizing radiation, whereas wild-type HRX promoted apoptosis—demonstrating a gain-of-function anti-apoptotic activity for leukemic HRX fusions. GADD34 also binds hSNF5/INI1.","method":"Yeast two-hybrid screening, co-immunoprecipitation, apoptosis assays (transfection, ionizing radiation treatment)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding confirmed by two methods, functional consequence demonstrated with three different fusion proteins","pmids":["10490642"],"is_preprint":false},{"year":1995,"finding":"The t(10;11) translocation consistently fuses the leucine zipper motif of AF10 onto the N-terminal region of HRX (KMT2A), with in-frame RT-PCR-confirmed HRX-AF10 fusion transcripts in all 8 cases tested; the consistent juxtaposition of AF10's leucine dimerization motif suggests a critical role for this domain in chimeric HRX protein function.","method":"Southern analysis, RT-PCR, sequence analysis of leukemia specimens","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — consistent molecular characterization across 8 cases with sequence validation","pmids":["7662954"],"is_preprint":false},{"year":1994,"finding":"The novel AF-1p gene on chromosome 1p32 (highly similar to murine eps15, a cytoplasmic phosphoprotein) is fused to HRX in t(1;11)(p32;q23), with the der(11) chromosome expressing 1368 N-terminal amino acids of HRX (including AT-hook, snRNP, and methyltransferase similarity domains) fused to almost all of AF-1p, expanding the catalog of structurally distinct HRX fusion partners.","method":"Molecular cloning, cDNA characterization, sequence analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular characterization of novel fusion, single lab","pmids":["8134107"],"is_preprint":false},{"year":1996,"finding":"ALL-1 (KMT2A) physically interacts with UNR (a protein containing multiple cold shock domains) through the N-terminal segment of ALL-1; the minimal UNR region required includes two cold shock domains and two intervening polypeptides, confirmed by yeast two-hybrid, in vitro binding studies, and co-immunoprecipitation from COS cells.","method":"Yeast two-hybrid screening, in vitro binding studies, co-immunoprecipitation in COS cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods confirming interaction, single lab","pmids":["8934551"],"is_preprint":false},{"year":2002,"finding":"ALL-1 (KMT2A) is a histone methyltransferase that assembles into a large (>1 MDa) multiprotein supercomplex containing ≥29 proteins including components of TFIID (TBP), SWI/SNF, NuRD, hSNF2H, and Sin3A complexes, as well as RNA processing factors; the complex remodels, acetylates, deacetylates, and methylates nucleosomes/free histones, with H3-K4 methyltransferase activity conferred by the ALL-1 SET domain; chromatin immunoprecipitation shows ALL-1 and complex components bound at the Hoxa9 promoter where H3-K4 is methylated and H3/H4 are acetylated.","method":"Biochemical purification, mass spectrometry identification of complex members, histone methyltransferase assays, chromatin immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution, enzymatic activity assay, and ChIP in one study; highly cited foundational paper","pmids":["12453419"],"is_preprint":false},{"year":2004,"finding":"MLL (KMT2A) was biochemically purified and shown to associate with a SET1-like histone methyltransferase complex including Ash2 homolog, host cell factor 1 (HCF-1), HCF-2, and the menin tumor suppressor (product of MEN1); menin interacts with MLL through a conserved binding motif in the MLL(N) subunit; abrogation of menin expression phenocopies loss of MLL function and reveals menin's critical role in maintaining Hox gene expression.","method":"Biochemical purification, co-immunoprecipitation, RNAi knockdown, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical purification + functional validation with menin knockdown, replicated by independent lab (Yokoyama 2005)","pmids":["15199122"],"is_preprint":false},{"year":2005,"finding":"MLL1 (KMT2A) forms a stable complex with the H4 K16 acetyltransferase MOF; interaction sites were mapped to MLL1 C-terminal and MOF zinc finger domains by reciprocal immunoprecipitation, cosedimentation, and cotransfection; both MLL1 methyltransferase (H3 K4) and MOF acetyltransferase (H4 K16) activities are required for optimal transcription activation on a chromatin template in vitro and on Hoxa9 in vivo.","method":"Immunoaffinity purification, reciprocal co-immunoprecipitation, cosedimentation, in vitro chromatin transcription assay, ChIP","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstitution on chromatin template with both activities tested, multiple orthogonal interaction methods","pmids":["15960975"],"is_preprint":false},{"year":2005,"finding":"WDR5, a common component of MLL1 (KMT2A), MLL2, and hSet1 complexes, directly associates with histone H3 di- and trimethylated at K4 and with K4-dimethylated nucleosomes; WDR5 is required for binding of the MLL1 methyltransferase complex to the K4-dimethylated H3 tail and for global H3 K4 trimethylation and Hox gene activation; WDR5 depletion in Xenopus causes developmental defects and abnormal Hox gene expression.","method":"Co-immunoprecipitation, nucleosome binding assays, RNAi knockdown in human cells, Xenopus morpholino knockdown","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct histone binding demonstrated, functional consequence in two model systems","pmids":["15960974"],"is_preprint":false},{"year":2005,"finding":"Menin (MEN1 product) is an essential oncogenic cofactor for MLL-associated leukemogenesis: oncogenic MLL fusion proteins retain a high-affinity menin-binding motif at their amino terminus, and this interaction is required for initiation of MLL-mediated leukemogenesis; acute genetic ablation of menin reverses aberrant Hox gene expression at MLL-menin promoter-associated complexes and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed blasts.","method":"Co-immunoprecipitation, retroviral transformation assays, conditional genetic ablation, gene expression analysis, ChIP","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — genetic ablation with molecular phenotype reversal, multiple orthogonal methods; highly cited","pmids":["16239140"],"is_preprint":false},{"year":2006,"finding":"Biochemical reconstitution of a functional four-component MLL1 (KMT2A) core complex (MLL1 SET domain + RbBP5 + Ash2L + WDR5) revealed that WDR5 mediates interactions of the MLL1 catalytic unit with both the structural platform (RbBP5/Ash2L) and the histone substrate; this mechanism is generalizable to the SET1-like family of H3K4 methyltransferases.","method":"Biochemical reconstitution, in vitro histone methyltransferase assay, crystal structure analysis of WDR5, in vivo transcriptional assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution + structural analysis + mutagenesis in a single study","pmids":["16878130"],"is_preprint":false},{"year":2007,"finding":"KMT2A (MLL) encodes a DNA-binding protein that methylates histone H3 lysine 4 (H3K4) and positively regulates gene expression including multiple Hox genes; leukemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity but gain the ability to efficiently transform hematopoietic cells into leukemia stem cells, linking chromatin modulation to stem-cell-like properties.","method":"Review synthesizing biochemical, genetic, and cell biological evidence from multiple studies","journal":"Nature reviews. Cancer","confidence":"High","confidence_rationale":"Tier 1-2 — synthesis of independently replicated mechanistic findings","pmids":["17957188"],"is_preprint":false},{"year":2011,"finding":"MLL-rearranged leukemia (KMT2A fusion) is dependent on aberrant H3K79 methylation by DOT1L: epigenetic profiling identified abnormal H3K79me2 specifically at MLL-AF9 fusion target loci in leukemia stem cells but not hematopoietic progenitors; inactivation of Dot1l selectively downregulated MLL translocation-associated gene expression signatures and suppressed MLL-AF9 leukemia in vivo, placing DOT1L as a critical downstream effector in the KMT2A fusion oncogenic pathway.","method":"ChIP-seq (H3K79me2, H3K4me3, H3K27me3, H3K36me3), genetic Dot1l inactivation, gene expression profiling, in vivo leukemia model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide epigenetic profiling plus genetic validation in vivo; highly cited","pmids":["21741597"],"is_preprint":false},{"year":1997,"finding":"The FEL (AF-4) component of HRX-FEL fusion proteins donates transcriptional activation sequences: the region of FEL encompassing amino acids 365–572, which is consistently retained in HRX-FEL fusions created by t(4;11), can activate transcription from a minimal adenoviral E1b promoter as a Gal4-FEL fusion, and this activity varies in a cell-type-specific manner.","method":"Transient transcriptional reporter assays with Gal4-fusion constructs in multiple cell lines","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct transcriptional activation assays mapping functional domain, single lab","pmids":["9403001"],"is_preprint":false},{"year":2014,"finding":"Kmt2a (MLL1) is essential for neural development in zebrafish: morpholino knockdown and dominant-negative expression caused downregulated proliferation of neural progenitors, premature neuronal differentiation, and impaired gliogenesis, establishing a role for KMT2A in regulating the balance between neural progenitor proliferation and differentiation.","method":"Morpholino antisense knockdown, dominant-negative expression, zebrafish embryo phenotyping","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined phenotypic readouts in vertebrate model, single lab","pmids":["25284327"],"is_preprint":false},{"year":2017,"finding":"KMT2A knockdown in glioblastoma cells (U-87 MG) promoted cell proliferation and increased DNA methylation of NOTCH1 and NOTCH3 promoters, reducing their expression; constitutively active NOTCH1 or NOTCH3 rescued KMT2A-knockdown-induced proliferation, defining a KMT2A-NOTCH negative regulatory cascade for glioblastoma cell proliferation, confirmed in vivo in zebrafish brain tumor transplantation.","method":"shRNA knockdown, methylation analysis, constitutively active NOTCH constructs, cell proliferation assays, zebrafish in vivo transplantation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established between KMT2A and NOTCH pathway with rescue experiment and in vivo validation","pmids":["28968975"],"is_preprint":false},{"year":2017,"finding":"KMT2A promotes melanoma cell growth by regulating the hTERT signaling pathway: KMT2A knockdown inhibited hTERT promoter activity and expression; hTERT overexpression rescued viability inhibition from KMT2A knockdown; KMT2A knockdown suppressed tumorsphere formation and cancer stem cell markers; confirmed in xenograft mouse models.","method":"shRNA knockdown, promoter-reporter assays, rescue overexpression, tumorsphere assay, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — promoter regulation plus rescue experiment and in vivo validation, single lab","pmids":["28726783"],"is_preprint":false},{"year":2020,"finding":"KMT2A and KDM5C (a H3K4 demethylase) functionally interact as a writer-eraser duo: despite opposite enzymatic activities, mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression; double mutation of Kmt2a and Kdm5c reversed dendritic morphology, key behavioral traits, and partially corrected altered transcriptomes and H3K4me landscapes, demonstrating mutually suppressive roles.","method":"Mouse genetic models (single and double knockouts), dendritic spine morphology, behavioral assays (aggression), transcriptomic profiling, H3K4 methylation analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in double-mutant animal model with molecular and behavioral readouts","pmids":["32483278"],"is_preprint":false},{"year":2017,"finding":"KMT2A variants associated with Wiedemann-Steiner syndrome cause loss of function: a splice variant (c.11322-1G>A) leads to deletion of the protein C-terminal; missense variants at the CXXC domain (p.Arg1154Trp) and transactivation domain (p.Met2853Arg) alter KMT2A target gene expression in patient fibroblasts, and the CXXC domain mutant shows disturbed subcellular distribution, confirming domain-specific functional requirements.","method":"Splice assay in patient cells, Western blotting, qRT-PCR of target genes in patient fibroblasts, subcellular localization studies","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2-3 — patient-derived primary cells with molecular phenotyping, two functional domains characterized","pmids":["29203834"],"is_preprint":false},{"year":2019,"finding":"The NUP98-KMT2A fusion (from inv(11)(p15q23)) has in vivo transforming activity: inducible transgenic mice developed myelodysplasia and transplantable AML after 80-week latency; iNUP98-KMT2A elevated LSK cell numbers, abrogated replicative senescence, caused G1 phase accumulation, and altered expression of Sirt1, Tert, Rbl2 and other cell-cycle genes; notably, unlike KMT2A-AF9, NUP98-KMT2A leukemic cells were resistant to menin and BET inhibitors and did not show HoxA-B-C upregulation.","method":"Inducible transgenic mouse model, repopulation assays, cell cycle analysis, gene expression profiling, pharmacological inhibitor testing","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model with molecular characterization and drug testing, single lab","pmids":["31558671"],"is_preprint":false},{"year":2023,"finding":"Menin-KMT2A/B complexes maintain bivalency at specific promoters distinct from their role at active genes: genetic loss or pharmacological inhibition of Menin paradoxically phenocopies polycomb disruption, causing derepression of bivalent genes in cancer cells and pluripotent stem cells; release of KMT2A from active genes following Menin targeting redistributes KMT2A to bivalent genes, altering the polycomb/KMT2A balance and facilitating bivalent gene activation.","method":"Whole-genome CRISPR-Cas9 screens, pharmacological Menin inhibition, ChIP-seq, gene expression profiling in cancer cells and PSCs","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide unbiased screen plus mechanistic validation with ChIP-seq across multiple cell types","pmids":["36635503"],"is_preprint":false},{"year":2023,"finding":"Proteasome inhibition targets the KMT2A transcriptional complex in infant KMT2A-rearranged ALL: proteasome inhibitor treatment depletes histone H2B monoubiquitination (H2Bub1) and H3K79me2 at KMT2A target genes and downregulates the KMT2A gene expression signature, demonstrating that the KMT2A transcriptional complex depends on proteasome-regulated ubiquitin pathways for its epigenetic activity.","method":"High-throughput drug screen in primary specimens, H2Bub1 and H3K79me2 ChIP, gene expression analysis, clinical response data","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for two histone marks plus gene signature analysis linking mechanism to drug effect","pmids":["36781850"],"is_preprint":false},{"year":2023,"finding":"MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation: KMT2A promotes NF-κB/RelA-mediated transcription of procoagulant factors (tissue factor/F3, PLAU, PLAUR) and proinflammatory cytokines, while suppressing IFN-α; MLL1-dependent regulation of coagulation-related factors was demonstrated in murine betacoronavirus (MHV-A59) infection models, with elevated MLL1 and coagulopathy factor expression in CD14+ monocytes from SARS-CoV-2-positive humans.","method":"Murine betacoronavirus infection model, conditional MLL1 ablation, ChIP, gene expression analysis, human SARS-CoV-2 patient samples","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — genetic ablation in vivo with molecular mechanism identified, validated in human samples","pmids":["36493338"],"is_preprint":false},{"year":2024,"finding":"KMT2A promotes the expression of METTL3 through H3K4me3 modification; METTL3-mediated m6A modification then reduces ATG4a RNA stability, impairing autophagy in nucleus pulposus cells (NPCs); restoration of autophagy inhibits GATA4 and reduces senescence-associated secretory phenotype, identifying a KMT2A→METTL3→m6A/ATG4a→autophagy→GATA4 axis in NPC senescence and intervertebral disc degeneration.","method":"ChIP for H3K4me3, m6A-seq, RNA stability assays, siRNA knockdown, IVDD patient samples and mouse models","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus m6A sequencing plus RNA stability assays establishing epistatic pathway, single lab","pmids":["39572532"],"is_preprint":false},{"year":2025,"finding":"Loss of KMT2C/D in urothelium causes redistribution of KMT2A-menin from KMT2D-localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes and impaired urothelial differentiation; this redistribution sensitizes cells to oncogenic transformation and reveals epidermal growth factor receptor vulnerability as a therapeutic target.","method":"Genetically engineered mouse models (Kmt2c/d knockout), ChIP-seq for KMT2A/menin and histone marks, nascent RNA transcription assays, EGFR inhibitor testing","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo genetic models with genome-wide ChIP-seq mechanistic characterization","pmids":["39806204"],"is_preprint":false},{"year":1995,"finding":"The ALL-1 (KMT2A) gene undergoes partial tandem duplication in acute leukemias with trisomy 11 as the sole chromosomal abnormality; genomic analysis showed Alu repeat involvement at the breakpoints, with splicing of exon 6 or exon 8 to exon 2, producing internally duplicated ALL-1 transcripts through a mechanism analogous to translocation-induced fusions.","method":"Southern blot, RT-PCR, genomic sequencing of breakpoint regions in leukemia patients","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular characterization of novel rearrangement mechanism in patient specimens","pmids":["7658717"],"is_preprint":false},{"year":2020,"finding":"KMT2A regulates cervical cancer cell growth via targeting VDAC1: KMT2A knockdown suppressed cell proliferation, migration, and induced PARP/caspase-dependent apoptosis alongside VDAC1 inhibition; VDAC1 overexpression rescued KMT2A-knockdown phenotypes; confirmed in xenograft models where KMT2A knockdown suppressed tumor growth through VDAC1 inhibition.","method":"shRNA knockdown, overexpression rescue, cell viability/migration/apoptosis assays, xenograft mouse model","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 — functional link between KMT2A and VDAC1 established only by knockdown/rescue without direct molecular mechanism (no ChIP or direct binding shown)","pmids":["32436862"],"is_preprint":false},{"year":2021,"finding":"A germline KMT2A G3131S mutation (in the SET domain region) in a familial MPN pedigree causes increased proliferation and colony formation in CRISPR-engineered K562 cells, with increased CD11b myeloid marker expression and decreased C-MYB expression at both RNA and protein levels, suggesting KMT2A regulates C-MYB to control myeloproliferation.","method":"CRISPR-Cas9 engineering of KMT2A G3131S K562 cells, colony formation, flow cytometry, RT-PCR, Western blotting, whole-exome sequencing","journal":"Annals of hematology","confidence":"Low","confidence_rationale":"Tier 3 — single engineered cell line model without direct molecular mechanism for C-MYB regulation","pmids":["34228147"],"is_preprint":false}],"current_model":"KMT2A (MLL1/HRX/ALL-1) encodes a large nuclear histone H3 lysine 4 (H3K4) methyltransferase whose SET domain catalytic activity is regulated within a multi-protein complex (including WDR5, RbBP5, Ash2L, menin, MOF, HCF-1, and >29 additional proteins) to maintain HOX gene expression and normal hematopoiesis and development; chromosomal translocations fuse the AT-hook/CXXC-containing N-terminus of KMT2A to diverse partner proteins (ENL, AF4, AF9, AF10, ELL, and >100 others) that contribute transcriptional activation domains and recruit DOT1L-mediated H3K79 methylation, driving leukemic transformation through gain-of-function immortalization of myeloid progenitors and anti-apoptotic activity, while the menin–KMT2A interaction is a critical dependency for both KMT2A-rearranged and NPM1-mutated acute leukemias and is now therapeutically targeted by FDA-approved menin inhibitors such as revumenib."},"narrative":{"teleology":[{"year":1991,"claim":"Identification of KMT2A (MLL/HRX/ALL-1) as the gene spanning 11q23 breakpoints in multiple acute leukemia translocations established it as the recurrent target of these rearrangements, opening the question of what normal function is disrupted.","evidence":"YAC clone mapping and molecular cloning across t(4;11), t(6;11), t(9;11), and t(11;19) leukemias","pmids":["1720549"],"confidence":"High","gaps":["No protein product or enzymatic activity characterized","Normal cellular function unknown"]},{"year":1992,"claim":"Cloning of the full-length KMT2A cDNA revealed it encodes a 431 kDa Drosophila trithorax homolog with AT-hook DNA-binding motifs and zinc finger domains, and that 11q23 translocations produce in-frame chimeric fusion proteins (e.g., HRX-ENL, HRX-AF4), suggesting gain-of-function oncoproteins rather than simple loss of function.","evidence":"Molecular cloning and sequence analysis of KMT2A and its fusion partners from leukemia cell lines","pmids":["1423624","1423625"],"confidence":"High","gaps":["No enzymatic activity demonstrated","Mechanism of fusion-mediated transformation unknown"]},{"year":1995,"claim":"Expanding the repertoire of KMT2A rearrangements to include partial tandem duplications and structurally diverse fusion partners (AF10, eps15) demonstrated that the consistent retention of N-terminal DNA-binding domains is the unifying molecular feature, while partner contributions vary widely.","evidence":"Southern blot, RT-PCR, and sequence analysis across multiple leukemia subtypes and novel fusion partners","pmids":["7662954","8134107","7658717","8389614"],"confidence":"High","gaps":["What the N-terminal domains contribute molecularly beyond DNA binding","Why structurally diverse partners all produce leukemia"]},{"year":1997,"claim":"Functional proof that KMT2A fusions are gain-of-function oncoproteins came from retroviral transduction showing HRX-ENL immortalizes myeloid progenitors and induces leukemia in mice, with the ENL portion required; fusion partners contribute transcriptional activation domains, and wild-type KMT2A localizes to punctate nuclear bodies.","evidence":"Retroviral gene transfer, serial replating, syngeneic/SCID mouse transplantation, immunocytochemistry, and Gal4-reporter transcription assays","pmids":["9250666","9129043","9403001"],"confidence":"High","gaps":["Enzymatic activity of wild-type KMT2A protein still unknown","Mechanism by which ENL contributes transformation activity unresolved"]},{"year":1999,"claim":"Discovery that KMT2A fusion proteins physically interact with GADD34 and abrogate radiation-induced apoptosis—while wild-type KMT2A promotes it—established anti-apoptotic gain-of-function as a second oncogenic mechanism beyond proliferation/immortalization.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and apoptosis assays with three different fusion proteins versus wild-type","pmids":["10490642"],"confidence":"High","gaps":["Whether GADD34 interaction is required for leukemogenesis in vivo","How wild-type KMT2A promotes apoptosis molecularly"]},{"year":2002,"claim":"Biochemical purification revealed KMT2A assembles a >1 MDa supercomplex with histone-modifying and chromatin-remodeling activities, and its SET domain directly methylates H3K4 at target loci including Hoxa9, finally establishing KMT2A as a histone methyltransferase.","evidence":"Biochemical purification, mass spectrometry, histone methyltransferase assays, and ChIP at Hoxa9","pmids":["12453419"],"confidence":"High","gaps":["Minimal complex required for catalytic activity not defined","Whether SET domain loss in fusion proteins is sufficient for transformation"]},{"year":2004,"claim":"Identification of menin as a stoichiometric KMT2A complex subunit, and demonstration that menin loss phenocopies KMT2A loss for HOX gene expression, established the menin–KMT2A interaction as essential for normal complex function.","evidence":"Biochemical purification, co-immunoprecipitation, RNAi knockdown, and gene expression analysis","pmids":["15199122"],"confidence":"High","gaps":["Whether menin is also required for oncogenic KMT2A fusions (answered the next year)"]},{"year":2005,"claim":"Three key advances defined the architecture and regulation of the KMT2A complex: WDR5 reads H3K4me2 to present substrate, MOF couples H4K16 acetylation with H3K4 methylation for transcriptional activation, and menin is an essential oncogenic cofactor whose ablation reverses HOX dysregulation and differentiation arrest in KMT2A-fusion leukemia.","evidence":"Reconstituted in vitro chromatin transcription, nucleosome binding assays, conditional genetic ablation, and ChIP","pmids":["15960974","15960975","16239140"],"confidence":"High","gaps":["Structural basis of menin–KMT2A interaction at atomic resolution","Whether menin inhibition is therapeutically feasible"]},{"year":2006,"claim":"Biochemical reconstitution of the minimal four-subunit core complex (MLL1-SET/WDR5/RbBP5/Ash2L) defined the catalytic module and showed WDR5 bridges enzyme and substrate, establishing the structural framework for the SET1-family methyltransferases.","evidence":"Reconstitution with purified recombinant proteins, in vitro HMT assay, crystal structure of WDR5","pmids":["16878130"],"confidence":"High","gaps":["Full-length complex structure not determined","Regulation of processivity (mono- vs. di- vs. trimethylation) unclear"]},{"year":2011,"claim":"Genome-wide epigenetic profiling resolved how KMT2A fusions activate transcription without H3K4 methyltransferase activity: MLL-AF9 fusion recruits DOT1L to deposit aberrant H3K79me2 at target loci, and DOT1L inactivation selectively suppresses fusion-driven leukemia, identifying DOT1L as the critical downstream effector.","evidence":"ChIP-seq for multiple histone marks, genetic Dot1l inactivation, gene expression profiling, in vivo leukemia model","pmids":["21741597"],"confidence":"High","gaps":["Whether all KMT2A fusion partners converge on DOT1L recruitment","Therapeutic window for DOT1L inhibition in patients"]},{"year":2017,"claim":"Germline loss-of-function KMT2A variants (splice, CXXC domain, transactivation domain) cause Wiedemann–Steiner syndrome with domain-specific molecular consequences, establishing KMT2A haploinsufficiency as a Mendelian developmental disorder mechanism.","evidence":"Splice assays, Western blot, qRT-PCR of target genes, and subcellular localization in patient fibroblasts","pmids":["29203834"],"confidence":"Medium","gaps":["Genotype–phenotype correlations across the full WSS mutation spectrum incomplete","Tissue-specific consequences of individual domain mutations not explored in vivo"]},{"year":2020,"claim":"Genetic epistasis between Kmt2a and the H3K4 demethylase Kdm5c established that KMT2A operates in a writer–eraser balance critical for dendritic spine morphology and behavior, extending its role beyond hematopoiesis to neuronal function.","evidence":"Single and double knockout mouse models with dendritic morphology, behavioral, transcriptomic, and H3K4me profiling","pmids":["32483278"],"confidence":"Medium","gaps":["Which specific neuronal target genes require the KMT2A–KDM5C balance","Whether this mechanism operates in human neurodevelopmental disease"]},{"year":2023,"claim":"Genome-wide CRISPR screens and ChIP-seq revealed that menin–KMT2A complexes maintain bivalent chromatin at developmental promoters; menin loss or pharmacological inhibition paradoxically derepresses bivalent genes by redistributing KMT2A, uncovering a mechanism by which menin inhibitors may have unintended activating effects beyond target gene silencing.","evidence":"Whole-genome CRISPR-Cas9 screens, pharmacological menin inhibition, ChIP-seq across cancer cells and pluripotent stem cells","pmids":["36635503"],"confidence":"High","gaps":["Long-term consequences of bivalent gene derepression during menin inhibitor therapy","Whether KMT2A redistribution varies across tissue types"]},{"year":2025,"claim":"Loss of KMT2C/D in urothelium causes compensatory redistribution of KMT2A–menin to CpG-high and bivalent promoters, derepressing immediate early genes and impairing differentiation, revealing inter-family crosstalk among KMT2 paralogs that creates therapeutic vulnerability to EGFR inhibition.","evidence":"Kmt2c/d knockout mouse models, KMT2A/menin ChIP-seq, nascent RNA transcription assays, EGFR inhibitor testing","pmids":["39806204"],"confidence":"High","gaps":["Whether paralog redistribution occurs in other epithelial cancers with KMT2C/D loss","Structural basis for preferential KMT2A targeting to CpG-rich promoters"]},{"year":null,"claim":"Major open questions include the atomic-resolution structure of the full-length KMT2A complex with menin and chromatin, the deterministic rules governing KMT2A mono- versus di- versus trimethylation processivity, and the long-term clinical consequences of menin inhibitor–induced KMT2A redistribution to bivalent promoters.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length KMT2A–menin–nucleosome cryo-EM structure","Processivity regulation by complex composition incompletely defined","Clinical impact of bivalent gene derepression during menin inhibitor therapy unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[12,14,15,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12,14,16,18,27]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12,15,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,12]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[12,15,19]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,14,15,17,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[12,14,16,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,21,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,16,19,26]}],"complexes":["MLL1/COMPASS-like complex (MLL1-SET/WDR5/RbBP5/Ash2L)","MLL1-MOF complex","Menin-KMT2A complex"],"partners":["WDR5","RBBP5","ASH2L","MEN1","KAT8","HCFC1","DOT1L","CSDE1"],"other_free_text":[]},"mechanistic_narrative":"KMT2A is a large histone H3 lysine 4 (H3K4) methyltransferase that functions within a multi-megadalton complex containing WDR5, RbBP5, Ash2L, menin, MOF, and HCF-1 to activate transcription at target loci including HOX genes, thereby maintaining normal hematopoiesis and neural development [PMID:12453419, PMID:15199122, PMID:16878130, PMID:15960975]. The menin–KMT2A interaction is essential both for normal HOX gene regulation and for leukemogenic transformation by KMT2A fusion oncoproteins, which retain the N-terminal AT-hook/CXXC DNA-binding domains but replace the SET domain with diverse transcriptional activation partners (ENL, AF4, AF9, AF10, ELL) that recruit DOT1L-dependent H3K79 methylation to enforce aberrant gene expression programs [PMID:16239140, PMID:21741597, PMID:9250666]. Chromosomal translocations at 11q23 creating KMT2A fusions are recurrent drivers of acute leukemia, while germline loss-of-function variants cause Wiedemann–Steiner syndrome [PMID:1423624, PMID:29203834]. Beyond hematopoiesis, KMT2A cooperates with KDM5C in an H3K4 writer–eraser balance that regulates dendritic spine morphology and behavior, and menin-dependent KMT2A redistribution maintains bivalent chromatin states at poised developmental promoters [PMID:32483278, PMID:36635503]."},"prefetch_data":{"uniprot":{"accession":"Q03164","full_name":"Histone-lysine N-methyltransferase 2A","aliases":["ALL-1","CXXC-type zinc finger protein 7","Cysteine methyltransferase KMT2A","Myeloid/lymphoid or mixed-lineage leukemia","Myeloid/lymphoid or mixed-lineage leukemia protein 1","Trithorax-like protein","Zinc finger protein HRX"],"length_aa":3969,"mass_kda":431.8,"function":"Histone methyltransferase that plays an essential role in early development and hematopoiesis (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:26886794). Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac) (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:24235145, PubMed:26886794). Catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:25561738, PubMed:26886794). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (PubMed:19187761, PubMed:26886794). Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9' (PubMed:19187761). Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (PubMed:20010842). Required for transcriptional activation of HOXA9 (PubMed:12453419, PubMed:20010842, PubMed:20677832). Promotes PPP1R15A-induced apoptosis (PubMed:10490642). Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-BMAL1 heterodimer (By similarity). Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-BMAL1 to chromatin (By similarity). Also has auto-methylation activity on Cys-3882 in absence of histone H3 substrate (PubMed:24235145)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q03164/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KMT2A","classification":"Not Classified","n_dependent_lines":170,"n_total_lines":1208,"dependency_fraction":0.14072847682119205},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"MYO1E","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KMT2A","total_profiled":1310},"omim":[{"mim_id":"620798","title":"FRY-LIKE TRANSCRIPTION COACTIVATOR; FRYL","url":"https://www.omim.org/entry/620798"},{"mim_id":"619635","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 19; ZFYVE19","url":"https://www.omim.org/entry/619635"},{"mim_id":"618950","title":"SULEIMAN-EL-HATTAB SYNDROME; SULEHS","url":"https://www.omim.org/entry/618950"},{"mim_id":"618738","title":"TUBULIN TYROSINE LIGASE-LIKE 4; TTLL4","url":"https://www.omim.org/entry/618738"},{"mim_id":"617215","title":"BPTF-ASSOCIATED CHROMATIN COMPLEX COMPONENT 1; BACC1","url":"https://www.omim.org/entry/617215"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KMT2A"},"hgnc":{"alias_symbol":["TRX1","HRX","ALL-1","HTRX1","CXXC7","MLL1A","MLL1","ALL1","HTRX"],"prev_symbol":["MLL"]},"alphafold":{"accession":"Q03164","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03164","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KMT2A","jax_strain_url":"https://www.jax.org/strain/search?query=KMT2A"},"sequence":{"accession":"Q03164","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03164.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03164/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03164"}},"corpus_meta":[{"pmid":"36922593","id":"PMC_36922593","title":"The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/21741597","citation_count":735,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15960974","id":"PMC_15960974","title":"WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15960974","citation_count":668,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16878130","id":"PMC_16878130","title":"Regulation of MLL1 H3K4 methyltransferase activity by its core components.","date":"2006","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16878130","citation_count":623,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29395067","id":"PMC_29395067","title":"High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29395067","citation_count":580,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12453419","id":"PMC_12453419","title":"ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.","date":"2002","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/12453419","citation_count":576,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16076867","id":"PMC_16076867","title":"Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16076867","citation_count":562,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16239140","id":"PMC_16239140","title":"The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16239140","citation_count":560,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15199122","id":"PMC_15199122","title":"Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15199122","citation_count":551,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15960975","id":"PMC_15960975","title":"Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15960975","citation_count":551,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1720549","id":"PMC_1720549","title":"Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1720549","citation_count":542,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53924,"output_tokens":4914,"usd":0.117741},"stage2":{"model":"claude-opus-4-6","input_tokens":8449,"output_tokens":3549,"usd":0.196455},"total_usd":0.723777,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":66834,"output_tokens":9023,"usd":0.167924},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12836,"output_tokens":3877,"usd":0.241657}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"HRX-ENL fusion protein directly immortalizes and leukemically transforms myeloid progenitors; the ENL component is required for in vitro transforming capability, as a deletion mutant lacking ENL fails to immortalize cells, demonstrating a gain-of-function mechanism for HRX fusion proteins.\",\n      \"method\": \"Retroviral transduction of hematopoietic stem cells, colony replating assays, syngeneic and SCID mouse leukemia models, deletion mutant analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — loss-of-function deletion mutant with defined cellular phenotype, in vivo validation, replicated across multiple fusion constructs\",\n      \"pmids\": [\"9250666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Wild-type HRX protein localizes to punctate nuclear structures (nuclear bodies) in cells; fusion with the eps15 (AF-1p) partner alters this localization to smaller, more numerous nuclear bodies exclusively in the nucleus, suggesting fusion-induced compartmentalization change as a mechanism of activation.\",\n      \"method\": \"Immunocytochemistry and cell fractionation of transfected cells and primary leukemia blasts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization experiment with functional interpretation, single lab\",\n      \"pmids\": [\"9041173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HRX protein is widely expressed in human tissues and localizes to punctate nuclear structures; chimeric HRX fusion proteins (HRX-ENL from t(11;19) and HRX-FEL from t(4;11)) migrate at sizes predicted from fusion mRNA analyses, confirming nuclear localization of both wild-type and fusion forms.\",\n      \"method\": \"Western blot and immunocytochemical analysis with polyclonal and monoclonal antibodies in cell lines and human tissues\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization by multiple antibody approaches, single lab\",\n      \"pmids\": [\"9129043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) directly interact with GADD34 protein (confirmed by yeast two-hybrid and co-immunoprecipitation), and co-expression of these fusion proteins inhibits GADD34-induced apoptosis after ionizing radiation, whereas wild-type HRX enhances apoptosis — demonstrating a gain-of-function anti-apoptotic mechanism for leukemic HRX fusions.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transfection/overexpression apoptosis assays with ionizing radiation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP plus functional apoptosis assay, multiple fusion proteins tested, comparison with wild-type\",\n      \"pmids\": [\"10490642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ALL-1/KMT2A N-terminal segment interacts with the UNR protein (containing multiple cold shock domains) as demonstrated by yeast two-hybrid screening, in vitro binding studies, and co-immunoprecipitation from COS cells, suggesting involvement of KMT2A in DNA/RNA interactions via UNR.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation from COS cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three orthogonal binding methods, single lab\",\n      \"pmids\": [\"8934551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The FEL (AF-4) component of the HRX-FEL fusion protein contains a transcriptional activation domain (amino acids 365-572) that is consistently retained in fusion proteins created by t(4;11) translocations, and this domain activates transcription in a cell-type-dependent manner, suggesting FEL contributes transcriptional effector properties to the chimeric oncogene.\",\n      \"method\": \"Gal4 fusion transactivation assays in multiple cell lines (Cos-7, MCF-7, REH, Gl-101A, A431)\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro transcriptional assay with domain mapping, multiple cell types tested\",\n      \"pmids\": [\"9403001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Chromosomal translocations fuse the N-terminal portion of HRX (containing AT-hook minor groove DNA-binding motifs) to FEL (AF4), a serine/proline-rich protein with GTP-binding and nuclear localization sequences, creating a chimeric transcription factor in t(4;11) leukemias.\",\n      \"method\": \"cDNA cloning and sequencing from t(4;11) leukemia cells, Southern and Northern blot analyses\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct molecular characterization of fusion gene structure, foundational paper\",\n      \"pmids\": [\"8443374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The AF10 gene, involved in t(10;11) translocation in AML, consistently fuses its leucine zipper dimerization motif onto the NH2-terminal region of HRX, implicating the leucine zipper motif as a critical functional element in the chimeric HRX-AF10 protein.\",\n      \"method\": \"Southern analysis, RT-PCR, and sequence analysis of adult, childhood, and infant leukemia samples\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural characterization confirmed in 8 cases, consistent fusion junction\",\n      \"pmids\": [\"7662954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kmt2a is required for neural progenitor proliferation and neuronal/glial differentiation in zebrafish; morpholino knockdown and dominant-negative expression cause reduced neural progenitor proliferation, premature neuronal differentiation, and impaired gliogenesis.\",\n      \"method\": \"Morpholino antisense knockdown and dominant-negative expression in zebrafish embryos\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific neurogenic phenotype in zebrafish ortholog model\",\n      \"pmids\": [\"25284327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A knockdown in glioblastoma U-87 MG cells promotes proliferation by reducing KMT2A-dependent H3K4 methylation at NOTCH1 and NOTCH3 promoters, increasing their DNA methylation and reducing expression; constitutively active NOTCH1 or NOTCH3 rescues the proliferation phenotype, placing KMT2A upstream of NOTCH signaling.\",\n      \"method\": \"KMT2A shRNA knockdown, promoter methylation analysis, constitutively active NOTCH rescue experiments, in vivo zebrafish xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"28968975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A promotes melanoma cell growth by activating hTERT promoter activity and expression; KMT2A knockdown suppresses hTERT expression and cell viability, and hTERT overexpression rescues the viability defect caused by KMT2A knockdown, placing KMT2A upstream of hTERT signaling.\",\n      \"method\": \"KMT2A knockdown, hTERT promoter reporter assays, rescue overexpression experiments, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue with promoter activity assay and in vivo validation, single lab\",\n      \"pmids\": [\"28726783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2A and KDM5C (an H3K4me demethylase) functionally oppose each other at H3K4 methylated loci; double mutation in mice reverses the dendritic spine reduction and behavioral traits (increased aggression) caused by single mutations, and partially corrects altered transcriptomes and H3K4me landscapes, establishing a writer-eraser balance at neuronal genes.\",\n      \"method\": \"Mouse genetic models (single and double Kmt2a/Kdm5c knockouts), dendritic spine morphology, behavioral assays, ChIP-seq for H3K4me, RNA-seq\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis with multiple orthogonal readouts (chromatin, transcriptomics, morphology, behavior), double-mutant rescue\",\n      \"pmids\": [\"32483278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2A knockdown in cervical cancer cells suppresses proliferation and migration and induces apoptosis via the PARP/caspase pathway; this is mediated through KMT2A-dependent regulation of VDAC1, as VDAC1 overexpression rescues the phenotype of KMT2A knockdown in vitro and in vivo.\",\n      \"method\": \"KMT2A knockdown, VDAC1 rescue overexpression, xenograft mouse model, apoptosis and proliferation assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue with in vivo validation, single lab\",\n      \"pmids\": [\"32436862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Menin inhibition (pharmacological or genetic) causes KMT2A/B to redistribute from active genes to bivalent promoters, altering the balance between KMT2A and polycomb complexes and paradoxically derepressing bivalent genes; CRISPR screens identified MTF2-PRC2.1, PCGF1-PRC1.1, and Menin-KMT2A/B as distinct regulators of bivalency.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screens, pharmacological menin inhibition, ChIP-seq, genetic KO in cancer cells and pluripotent stem cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR epistasis screens combined with ChIP-seq and genetic validation, multiple orthogonal approaches\",\n      \"pmids\": [\"36635503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The menin-KMT2A complex occupies chromatin at target gene promoters (including MEIS1 and FLT3); bleximenib (JNJ-75276617) inhibits the protein-protein interaction between menin and KMT2A, displacing the complex from chromatin and reducing target gene expression in KMT2A-rearranged and NPM1-mutant AML.\",\n      \"method\": \"ChIP-seq, gene expression analysis, xenograft models, co-crystal structure of menin with inhibitor\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — ChIP-seq showing chromatin displacement, co-crystal structure, in vivo xenograft validation\",\n      \"pmids\": [\"38905635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proteasome inhibition in KMT2A-rearranged ALL depletes histone H2B monoubiquitination (H2Bub1) and H3K79 dimethylation (H3K79me2) at KMT2A target genes and downregulates the KMT2A gene expression signature, indicating proteasome activity is required for maintenance of the KMT2A transcriptional complex.\",\n      \"method\": \"High-throughput drug screen in primary specimens, ChIP analysis of H2Bub1 and H3K79me2, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-based mechanistic data with drug screen and clinical correlate, single lab\",\n      \"pmids\": [\"36781850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MLL1/KMT2A in monocytes/macrophages drives NF-κB/RelA-mediated transcription of procoagulant factors (tissue factor, urokinase, urokinase receptor) and proinflammatory cytokines, while suppressing IFN-α, in a murine coronavirus infection model; MLL1-deficient monocytes show reduced coagulopathy-related gene expression.\",\n      \"method\": \"Conditional MLL1 knockout in monocytes/macrophages, in vitro transcription assays, murine betacoronavirus (MHV-A59) infection model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined transcriptional and coagulation phenotype, single lab\",\n      \"pmids\": [\"36493338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2A promotes METTL3 expression through H3K4me3 modification; METTL3-mediated m6A modification then reduces ATG4a RNA stability, impairing autophagy in nucleus pulposus cells and promoting GATA4-driven senescence and SASP, establishing a KMT2A→H3K4me3→METTL3→m6A/ATG4a→autophagy→GATA4 axis in IVDD.\",\n      \"method\": \"KMT2A and METTL3 silencing, ChIP-seq for H3K4me3, m6A-seq, RNA stability assays, autophagic flux assays in nucleus pulposus cells\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal epigenomic methods establishing pathway, single lab\",\n      \"pmids\": [\"39572532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KMT2D loss in urothelium causes redistribution of KMT2A-menin complex from KMT2D-localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes; this was shown alongside loss of H3K4me1 and H3K27ac at urothelial lineage enhancers.\",\n      \"method\": \"Genetically engineered mouse models (Kmt2c/d knockout), ChIP-seq for H3K4me1/H3K27ac, KMT2A ChIP-seq, nascent RNA transcription assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic model combined with ChIP-seq showing direct chromatin redistribution, multiple orthogonal methods\",\n      \"pmids\": [\"39806204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NUP98-KMT2A fusion protein has in vivo transforming activity in inducible transgenic mice, causing myelodysplasia and AML with expanded LSK cells that outcompete wildtype cells in repopulation assays; mechanistically, the fusion interferes with cell cycle progression (G1 accumulation) and alters expression of Sirt1, Tert, Rbl2, Twist1, Vim, and Prkcd rather than primarily upregulating HoxA-B-C genes.\",\n      \"method\": \"Inducible transgenic mouse model, bone marrow repopulation assays, cell cycle analysis, gene expression profiling in MEFs and hematopoietic progenitors\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with defined mechanistic phenotype, single lab\",\n      \"pmids\": [\"31558671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A missense variants at the CXXC domain (p.Arg1154Trp) and transactivation domain (p.Met2853Arg) alter expression of KMT2A target genes in patient fibroblasts; the CXXC domain mutant also shows disturbed subcellular distribution of KMT2A, suggesting both domains are required for normal KMT2A function.\",\n      \"method\": \"Patient-derived fibroblasts with splice/missense variants, gene expression analysis of KMT2A targets, immunofluorescence for subcellular localization\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cells with domain-specific functional readouts, single lab\",\n      \"pmids\": [\"29203834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2A (HRX/MLL1/ALL-1) is a histone H3K4 methyltransferase that forms a complex with menin and occupies active gene and bivalent promoter chromatin to maintain transcriptional programs; chromosomal translocations fuse the KMT2A N-terminal DNA-binding and AT-hook domains to partner proteins (e.g., ENL, AF4, AF10, AF9) that contribute transcriptional activation domains, creating chimeric oncoproteins that gain anti-apoptotic function and aberrantly sustain HOXA/MEIS1/FLT3 expression in leukemia, while the menin–KMT2A interaction positions the complex at active enhancers and, when disrupted, causes its redistribution to bivalent promoters, derepressing polycomb-silenced genes.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers.\n\n**Classification notes:**\n- Papers [3], [18], [22], [31], [37], [39], [43-50], [52], [58-60], [62], [78-79], [81], [83], [85], [89-90], [99] in the main corpus are about TRX1 (thioredoxin-1) — SYMBOL COLLISION or unrelated genes → EXCLUDE\n- Papers [4] (PCM1/MBD protein) describes PCM1 interacting with HRX → partially relevant but mainly about a different protein\n- Papers about general genomics/proteomics (gene2pubmed [1-11], [15-17], [19-20], [22], [24]) → EXCLUDE (not mechanistic for KMT2A)\n- All papers clearly about KMT2A/HRX/ALL-1/MLL → KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"KMT2A (HRX/ALL-1/MLL) was identified as a human homolog of Drosophila trithorax, encoding a predicted 431 kDa protein with AT-hook DNA-binding motifs (related to HMG proteins) and zinc finger domains; 11q23 translocations disrupt the HRX gene between these two motifs, generating chimeric fusion transcripts (e.g., HRX-ENL) from both derivative chromosomes, implicating KMT2A in multilineage leukemia through DNA binding at AT-rich sites.\",\n      \"method\": \"Molecular cloning, Southern/Northern blotting, sequence analysis, cell line characterization\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — original discovery with multiple orthogonal methods, highly cited foundational paper\",\n      \"pmids\": [\"1423624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The t(4;11) translocation fuses ALL-1 (KMT2A) on chromosome 11q23 to the AF-4 gene on chromosome 4, creating reciprocal chimeric proteins; the ALL-1 gene spans ~100 kb with at least 21 exons, and the breakpoint cluster region spans 8 kb, consistently producing in-frame fusion oncoproteins.\",\n      \"method\": \"Molecular cloning, Southern blotting, Northern blotting, sequence analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational cloning paper with multiple methods, independently replicated\",\n      \"pmids\": [\"1423625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The MLL gene was identified spanning the breakpoint in 11q23 translocations [t(4;11), t(6;11), t(9;11), t(11;19)] associated with acute leukemias, establishing KMT2A as the recurrent target of these rearrangements.\",\n      \"method\": \"YAC clone mapping, molecular cloning, transcription unit identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original locus identification, replicated across multiple translocations\",\n      \"pmids\": [\"1720549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HRX rearrangements occur in at least nine distinct partner loci across diverse 11q23 abnormalities in de novo and therapy-related leukemias; all breakpoints localize to an 8-kb region encompassing exons 5–11 of HRX, indicating that fusion proteins consistently retain similar N-terminal HRX sequences.\",\n      \"method\": \"Southern blot analysis across 35 leukemia cases\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large case series with consistent molecular mapping across multiple partner genes\",\n      \"pmids\": [\"8389614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The t(4;11) translocation creates an HRX-FEL fusion where 913 C-terminal amino acids of FEL (AF-4), a basic, serine/proline-rich protein containing GTP-binding and nuclear localization sequences, are fused in-frame to the N-terminal DNA-binding portion of HRX, generating a chimeric transcription factor.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blotting\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct molecular characterization of fusion protein structure\",\n      \"pmids\": [\"8443374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HRX (KMT2A) protein is widely expressed in human tissues with punctate nuclear distribution, localizing to discrete nuclear structures/bodies in both normal and leukemic cells; chimeric HRX fusion proteins (HRX-ENL, HRX-FEL) retain nuclear localization with sizes corresponding to predicted fusion protein molecular weights.\",\n      \"method\": \"Immunocytochemistry with polyclonal/monoclonal antibodies, Western blotting of cell lines with t(11;19) and t(4;11) translocations\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization with validated antibodies across multiple cell lines and tissues\",\n      \"pmids\": [\"9129043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Retroviral transduction of HRX-ENL into hematopoietic stem-cell-enriched populations dramatically enhanced myeloid colony formation, enabled serial replating (≥3 generations), established immortalized myelomonocytic cell lines, and induced myeloid leukemias in syngeneic and SCID recipients; the ENL component was required since a deletion mutant lacking ENL had no transforming activity, demonstrating gain-of-function leukemogenic activity of the HRX-ENL fusion.\",\n      \"method\": \"Retroviral gene transfer, in vitro colony replating assays, suspension culture immortalization, syngeneic/SCID mouse leukemia transplantation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in vitro and in vivo with deletion mutant controls, highly cited\",\n      \"pmids\": [\"9250666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The HRX/ALL1-eps15 fusion protein (from t(1;11)) localizes exclusively to the nucleus in smaller, more numerous nuclear bodies compared to wild-type HRX/ALL1 (which localizes to both cytoplasm and nucleus with larger nuclear bodies), indicating that fusion with eps15 alters subcellular compartmentalization of HRX/ALL1 as a potential activation mechanism.\",\n      \"method\": \"Immunofluorescence microscopy in transfected cells and leukemia blasts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization experiment comparing wild-type vs. fusion protein, single lab\",\n      \"pmids\": [\"9041173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Wild-type HRX and leukemic HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) directly interact with the GADD34 protein (confirmed by yeast two-hybrid and co-immunoprecipitation in human cells); coexpression of HRX fusion proteins abrogated GADD34-induced apoptosis following ionizing radiation, whereas wild-type HRX promoted apoptosis—demonstrating a gain-of-function anti-apoptotic activity for leukemic HRX fusions. GADD34 also binds hSNF5/INI1.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, apoptosis assays (transfection, ionizing radiation treatment)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed by two methods, functional consequence demonstrated with three different fusion proteins\",\n      \"pmids\": [\"10490642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The t(10;11) translocation consistently fuses the leucine zipper motif of AF10 onto the N-terminal region of HRX (KMT2A), with in-frame RT-PCR-confirmed HRX-AF10 fusion transcripts in all 8 cases tested; the consistent juxtaposition of AF10's leucine dimerization motif suggests a critical role for this domain in chimeric HRX protein function.\",\n      \"method\": \"Southern analysis, RT-PCR, sequence analysis of leukemia specimens\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — consistent molecular characterization across 8 cases with sequence validation\",\n      \"pmids\": [\"7662954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The novel AF-1p gene on chromosome 1p32 (highly similar to murine eps15, a cytoplasmic phosphoprotein) is fused to HRX in t(1;11)(p32;q23), with the der(11) chromosome expressing 1368 N-terminal amino acids of HRX (including AT-hook, snRNP, and methyltransferase similarity domains) fused to almost all of AF-1p, expanding the catalog of structurally distinct HRX fusion partners.\",\n      \"method\": \"Molecular cloning, cDNA characterization, sequence analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular characterization of novel fusion, single lab\",\n      \"pmids\": [\"8134107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"ALL-1 (KMT2A) physically interacts with UNR (a protein containing multiple cold shock domains) through the N-terminal segment of ALL-1; the minimal UNR region required includes two cold shock domains and two intervening polypeptides, confirmed by yeast two-hybrid, in vitro binding studies, and co-immunoprecipitation from COS cells.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro binding studies, co-immunoprecipitation in COS cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods confirming interaction, single lab\",\n      \"pmids\": [\"8934551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ALL-1 (KMT2A) is a histone methyltransferase that assembles into a large (>1 MDa) multiprotein supercomplex containing ≥29 proteins including components of TFIID (TBP), SWI/SNF, NuRD, hSNF2H, and Sin3A complexes, as well as RNA processing factors; the complex remodels, acetylates, deacetylates, and methylates nucleosomes/free histones, with H3-K4 methyltransferase activity conferred by the ALL-1 SET domain; chromatin immunoprecipitation shows ALL-1 and complex components bound at the Hoxa9 promoter where H3-K4 is methylated and H3/H4 are acetylated.\",\n      \"method\": \"Biochemical purification, mass spectrometry identification of complex members, histone methyltransferase assays, chromatin immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution, enzymatic activity assay, and ChIP in one study; highly cited foundational paper\",\n      \"pmids\": [\"12453419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MLL (KMT2A) was biochemically purified and shown to associate with a SET1-like histone methyltransferase complex including Ash2 homolog, host cell factor 1 (HCF-1), HCF-2, and the menin tumor suppressor (product of MEN1); menin interacts with MLL through a conserved binding motif in the MLL(N) subunit; abrogation of menin expression phenocopies loss of MLL function and reveals menin's critical role in maintaining Hox gene expression.\",\n      \"method\": \"Biochemical purification, co-immunoprecipitation, RNAi knockdown, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical purification + functional validation with menin knockdown, replicated by independent lab (Yokoyama 2005)\",\n      \"pmids\": [\"15199122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MLL1 (KMT2A) forms a stable complex with the H4 K16 acetyltransferase MOF; interaction sites were mapped to MLL1 C-terminal and MOF zinc finger domains by reciprocal immunoprecipitation, cosedimentation, and cotransfection; both MLL1 methyltransferase (H3 K4) and MOF acetyltransferase (H4 K16) activities are required for optimal transcription activation on a chromatin template in vitro and on Hoxa9 in vivo.\",\n      \"method\": \"Immunoaffinity purification, reciprocal co-immunoprecipitation, cosedimentation, in vitro chromatin transcription assay, ChIP\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution on chromatin template with both activities tested, multiple orthogonal interaction methods\",\n      \"pmids\": [\"15960975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"WDR5, a common component of MLL1 (KMT2A), MLL2, and hSet1 complexes, directly associates with histone H3 di- and trimethylated at K4 and with K4-dimethylated nucleosomes; WDR5 is required for binding of the MLL1 methyltransferase complex to the K4-dimethylated H3 tail and for global H3 K4 trimethylation and Hox gene activation; WDR5 depletion in Xenopus causes developmental defects and abnormal Hox gene expression.\",\n      \"method\": \"Co-immunoprecipitation, nucleosome binding assays, RNAi knockdown in human cells, Xenopus morpholino knockdown\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct histone binding demonstrated, functional consequence in two model systems\",\n      \"pmids\": [\"15960974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Menin (MEN1 product) is an essential oncogenic cofactor for MLL-associated leukemogenesis: oncogenic MLL fusion proteins retain a high-affinity menin-binding motif at their amino terminus, and this interaction is required for initiation of MLL-mediated leukemogenesis; acute genetic ablation of menin reverses aberrant Hox gene expression at MLL-menin promoter-associated complexes and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed blasts.\",\n      \"method\": \"Co-immunoprecipitation, retroviral transformation assays, conditional genetic ablation, gene expression analysis, ChIP\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic ablation with molecular phenotype reversal, multiple orthogonal methods; highly cited\",\n      \"pmids\": [\"16239140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Biochemical reconstitution of a functional four-component MLL1 (KMT2A) core complex (MLL1 SET domain + RbBP5 + Ash2L + WDR5) revealed that WDR5 mediates interactions of the MLL1 catalytic unit with both the structural platform (RbBP5/Ash2L) and the histone substrate; this mechanism is generalizable to the SET1-like family of H3K4 methyltransferases.\",\n      \"method\": \"Biochemical reconstitution, in vitro histone methyltransferase assay, crystal structure analysis of WDR5, in vivo transcriptional assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution + structural analysis + mutagenesis in a single study\",\n      \"pmids\": [\"16878130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KMT2A (MLL) encodes a DNA-binding protein that methylates histone H3 lysine 4 (H3K4) and positively regulates gene expression including multiple Hox genes; leukemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity but gain the ability to efficiently transform hematopoietic cells into leukemia stem cells, linking chromatin modulation to stem-cell-like properties.\",\n      \"method\": \"Review synthesizing biochemical, genetic, and cell biological evidence from multiple studies\",\n      \"journal\": \"Nature reviews. Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — synthesis of independently replicated mechanistic findings\",\n      \"pmids\": [\"17957188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MLL-rearranged leukemia (KMT2A fusion) is dependent on aberrant H3K79 methylation by DOT1L: epigenetic profiling identified abnormal H3K79me2 specifically at MLL-AF9 fusion target loci in leukemia stem cells but not hematopoietic progenitors; inactivation of Dot1l selectively downregulated MLL translocation-associated gene expression signatures and suppressed MLL-AF9 leukemia in vivo, placing DOT1L as a critical downstream effector in the KMT2A fusion oncogenic pathway.\",\n      \"method\": \"ChIP-seq (H3K79me2, H3K4me3, H3K27me3, H3K36me3), genetic Dot1l inactivation, gene expression profiling, in vivo leukemia model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide epigenetic profiling plus genetic validation in vivo; highly cited\",\n      \"pmids\": [\"21741597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The FEL (AF-4) component of HRX-FEL fusion proteins donates transcriptional activation sequences: the region of FEL encompassing amino acids 365–572, which is consistently retained in HRX-FEL fusions created by t(4;11), can activate transcription from a minimal adenoviral E1b promoter as a Gal4-FEL fusion, and this activity varies in a cell-type-specific manner.\",\n      \"method\": \"Transient transcriptional reporter assays with Gal4-fusion constructs in multiple cell lines\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct transcriptional activation assays mapping functional domain, single lab\",\n      \"pmids\": [\"9403001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kmt2a (MLL1) is essential for neural development in zebrafish: morpholino knockdown and dominant-negative expression caused downregulated proliferation of neural progenitors, premature neuronal differentiation, and impaired gliogenesis, establishing a role for KMT2A in regulating the balance between neural progenitor proliferation and differentiation.\",\n      \"method\": \"Morpholino antisense knockdown, dominant-negative expression, zebrafish embryo phenotyping\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined phenotypic readouts in vertebrate model, single lab\",\n      \"pmids\": [\"25284327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A knockdown in glioblastoma cells (U-87 MG) promoted cell proliferation and increased DNA methylation of NOTCH1 and NOTCH3 promoters, reducing their expression; constitutively active NOTCH1 or NOTCH3 rescued KMT2A-knockdown-induced proliferation, defining a KMT2A-NOTCH negative regulatory cascade for glioblastoma cell proliferation, confirmed in vivo in zebrafish brain tumor transplantation.\",\n      \"method\": \"shRNA knockdown, methylation analysis, constitutively active NOTCH constructs, cell proliferation assays, zebrafish in vivo transplantation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established between KMT2A and NOTCH pathway with rescue experiment and in vivo validation\",\n      \"pmids\": [\"28968975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A promotes melanoma cell growth by regulating the hTERT signaling pathway: KMT2A knockdown inhibited hTERT promoter activity and expression; hTERT overexpression rescued viability inhibition from KMT2A knockdown; KMT2A knockdown suppressed tumorsphere formation and cancer stem cell markers; confirmed in xenograft mouse models.\",\n      \"method\": \"shRNA knockdown, promoter-reporter assays, rescue overexpression, tumorsphere assay, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter regulation plus rescue experiment and in vivo validation, single lab\",\n      \"pmids\": [\"28726783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2A and KDM5C (a H3K4 demethylase) functionally interact as a writer-eraser duo: despite opposite enzymatic activities, mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression; double mutation of Kmt2a and Kdm5c reversed dendritic morphology, key behavioral traits, and partially corrected altered transcriptomes and H3K4me landscapes, demonstrating mutually suppressive roles.\",\n      \"method\": \"Mouse genetic models (single and double knockouts), dendritic spine morphology, behavioral assays (aggression), transcriptomic profiling, H3K4 methylation analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in double-mutant animal model with molecular and behavioral readouts\",\n      \"pmids\": [\"32483278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A variants associated with Wiedemann-Steiner syndrome cause loss of function: a splice variant (c.11322-1G>A) leads to deletion of the protein C-terminal; missense variants at the CXXC domain (p.Arg1154Trp) and transactivation domain (p.Met2853Arg) alter KMT2A target gene expression in patient fibroblasts, and the CXXC domain mutant shows disturbed subcellular distribution, confirming domain-specific functional requirements.\",\n      \"method\": \"Splice assay in patient cells, Western blotting, qRT-PCR of target genes in patient fibroblasts, subcellular localization studies\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — patient-derived primary cells with molecular phenotyping, two functional domains characterized\",\n      \"pmids\": [\"29203834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The NUP98-KMT2A fusion (from inv(11)(p15q23)) has in vivo transforming activity: inducible transgenic mice developed myelodysplasia and transplantable AML after 80-week latency; iNUP98-KMT2A elevated LSK cell numbers, abrogated replicative senescence, caused G1 phase accumulation, and altered expression of Sirt1, Tert, Rbl2 and other cell-cycle genes; notably, unlike KMT2A-AF9, NUP98-KMT2A leukemic cells were resistant to menin and BET inhibitors and did not show HoxA-B-C upregulation.\",\n      \"method\": \"Inducible transgenic mouse model, repopulation assays, cell cycle analysis, gene expression profiling, pharmacological inhibitor testing\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with molecular characterization and drug testing, single lab\",\n      \"pmids\": [\"31558671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Menin-KMT2A/B complexes maintain bivalency at specific promoters distinct from their role at active genes: genetic loss or pharmacological inhibition of Menin paradoxically phenocopies polycomb disruption, causing derepression of bivalent genes in cancer cells and pluripotent stem cells; release of KMT2A from active genes following Menin targeting redistributes KMT2A to bivalent genes, altering the polycomb/KMT2A balance and facilitating bivalent gene activation.\",\n      \"method\": \"Whole-genome CRISPR-Cas9 screens, pharmacological Menin inhibition, ChIP-seq, gene expression profiling in cancer cells and PSCs\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide unbiased screen plus mechanistic validation with ChIP-seq across multiple cell types\",\n      \"pmids\": [\"36635503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proteasome inhibition targets the KMT2A transcriptional complex in infant KMT2A-rearranged ALL: proteasome inhibitor treatment depletes histone H2B monoubiquitination (H2Bub1) and H3K79me2 at KMT2A target genes and downregulates the KMT2A gene expression signature, demonstrating that the KMT2A transcriptional complex depends on proteasome-regulated ubiquitin pathways for its epigenetic activity.\",\n      \"method\": \"High-throughput drug screen in primary specimens, H2Bub1 and H3K79me2 ChIP, gene expression analysis, clinical response data\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for two histone marks plus gene signature analysis linking mechanism to drug effect\",\n      \"pmids\": [\"36781850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation: KMT2A promotes NF-κB/RelA-mediated transcription of procoagulant factors (tissue factor/F3, PLAU, PLAUR) and proinflammatory cytokines, while suppressing IFN-α; MLL1-dependent regulation of coagulation-related factors was demonstrated in murine betacoronavirus (MHV-A59) infection models, with elevated MLL1 and coagulopathy factor expression in CD14+ monocytes from SARS-CoV-2-positive humans.\",\n      \"method\": \"Murine betacoronavirus infection model, conditional MLL1 ablation, ChIP, gene expression analysis, human SARS-CoV-2 patient samples\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic ablation in vivo with molecular mechanism identified, validated in human samples\",\n      \"pmids\": [\"36493338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2A promotes the expression of METTL3 through H3K4me3 modification; METTL3-mediated m6A modification then reduces ATG4a RNA stability, impairing autophagy in nucleus pulposus cells (NPCs); restoration of autophagy inhibits GATA4 and reduces senescence-associated secretory phenotype, identifying a KMT2A→METTL3→m6A/ATG4a→autophagy→GATA4 axis in NPC senescence and intervertebral disc degeneration.\",\n      \"method\": \"ChIP for H3K4me3, m6A-seq, RNA stability assays, siRNA knockdown, IVDD patient samples and mouse models\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus m6A sequencing plus RNA stability assays establishing epistatic pathway, single lab\",\n      \"pmids\": [\"39572532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of KMT2C/D in urothelium causes redistribution of KMT2A-menin from KMT2D-localized enhancers to CpG-high and bivalent promoters, resulting in derepression of signal-induced immediate early genes and impaired urothelial differentiation; this redistribution sensitizes cells to oncogenic transformation and reveals epidermal growth factor receptor vulnerability as a therapeutic target.\",\n      \"method\": \"Genetically engineered mouse models (Kmt2c/d knockout), ChIP-seq for KMT2A/menin and histone marks, nascent RNA transcription assays, EGFR inhibitor testing\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo genetic models with genome-wide ChIP-seq mechanistic characterization\",\n      \"pmids\": [\"39806204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The ALL-1 (KMT2A) gene undergoes partial tandem duplication in acute leukemias with trisomy 11 as the sole chromosomal abnormality; genomic analysis showed Alu repeat involvement at the breakpoints, with splicing of exon 6 or exon 8 to exon 2, producing internally duplicated ALL-1 transcripts through a mechanism analogous to translocation-induced fusions.\",\n      \"method\": \"Southern blot, RT-PCR, genomic sequencing of breakpoint regions in leukemia patients\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular characterization of novel rearrangement mechanism in patient specimens\",\n      \"pmids\": [\"7658717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2A regulates cervical cancer cell growth via targeting VDAC1: KMT2A knockdown suppressed cell proliferation, migration, and induced PARP/caspase-dependent apoptosis alongside VDAC1 inhibition; VDAC1 overexpression rescued KMT2A-knockdown phenotypes; confirmed in xenograft models where KMT2A knockdown suppressed tumor growth through VDAC1 inhibition.\",\n      \"method\": \"shRNA knockdown, overexpression rescue, cell viability/migration/apoptosis assays, xenograft mouse model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional link between KMT2A and VDAC1 established only by knockdown/rescue without direct molecular mechanism (no ChIP or direct binding shown)\",\n      \"pmids\": [\"32436862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A germline KMT2A G3131S mutation (in the SET domain region) in a familial MPN pedigree causes increased proliferation and colony formation in CRISPR-engineered K562 cells, with increased CD11b myeloid marker expression and decreased C-MYB expression at both RNA and protein levels, suggesting KMT2A regulates C-MYB to control myeloproliferation.\",\n      \"method\": \"CRISPR-Cas9 engineering of KMT2A G3131S K562 cells, colony formation, flow cytometry, RT-PCR, Western blotting, whole-exome sequencing\",\n      \"journal\": \"Annals of hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single engineered cell line model without direct molecular mechanism for C-MYB regulation\",\n      \"pmids\": [\"34228147\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2A (MLL1/HRX/ALL-1) encodes a large nuclear histone H3 lysine 4 (H3K4) methyltransferase whose SET domain catalytic activity is regulated within a multi-protein complex (including WDR5, RbBP5, Ash2L, menin, MOF, HCF-1, and >29 additional proteins) to maintain HOX gene expression and normal hematopoiesis and development; chromosomal translocations fuse the AT-hook/CXXC-containing N-terminus of KMT2A to diverse partner proteins (ENL, AF4, AF9, AF10, ELL, and >100 others) that contribute transcriptional activation domains and recruit DOT1L-mediated H3K79 methylation, driving leukemic transformation through gain-of-function immortalization of myeloid progenitors and anti-apoptotic activity, while the menin–KMT2A interaction is a critical dependency for both KMT2A-rearranged and NPM1-mutated acute leukemias and is now therapeutically targeted by FDA-approved menin inhibitors such as revumenib.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KMT2A is a histone H3 lysine 4 (H3K4) methyltransferase that, in complex with menin, occupies active gene promoters and enhancers to maintain transcriptional programs essential for hematopoiesis, neurogenesis, and innate immune gene regulation [PMID:36635503, PMID:38905635, PMID:25284327, PMID:36493338]. The menin–KMT2A interaction anchors the complex at chromatin; disruption of this interaction causes KMT2A redistribution from active enhancers to bivalent promoters, paradoxically derepressing polycomb-silenced genes [PMID:36635503, PMID:39806204]. KMT2A functionally opposes the H3K4 demethylase KDM5C, and this writer–eraser balance at neuronal gene loci controls dendritic spine morphology and behavior [PMID:32483278]. Chromosomal translocations fuse the KMT2A N-terminal AT-hook/CXXC DNA-binding region to diverse partner transcriptional activation or dimerization domains (ENL, AF4, AF9, AF10), generating chimeric oncoproteins that immortalize hematopoietic progenitors, gain anti-apoptotic function, and sustain aberrant HOXA/MEIS1/FLT3 expression in leukemia [PMID:9250666, PMID:8443374, PMID:10490642, PMID:38905635].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Cloning of the t(4;11) fusion gene revealed that translocations join KMT2A's N-terminal AT-hook DNA-binding region to partner proteins, establishing the chimeric transcription factor paradigm for KMT2A-rearranged leukemias.\",\n      \"evidence\": \"cDNA cloning and sequencing from t(4;11) leukemia cells\",\n      \"pmids\": [\"8443374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional validation that the fusion protein has transcriptional or transforming activity\", \"Mechanism of partner gene contribution unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Structural analysis of t(10;11) showed that diverse partners (AF10's leucine zipper) are consistently fused to the KMT2A N-terminus, suggesting different partner functional domains contribute distinct effector properties to fusion oncoproteins.\",\n      \"evidence\": \"Southern analysis, RT-PCR, and sequencing across eight leukemia cases\",\n      \"pmids\": [\"7662954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct test of leucine zipper requirement for transformation\", \"Whether dimerization per se drives oncogenesis untested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Functional reconstitution established that KMT2A fusion proteins are gain-of-function oncogenes: HRX-ENL directly immortalizes myeloid progenitors, and the ENL portion is required, resolving whether fusions are loss-of-function or gain-of-function.\",\n      \"evidence\": \"Retroviral transduction of hematopoietic stem cells with wild-type and deletion mutants, colony replating assays, syngeneic and SCID mouse models\",\n      \"pmids\": [\"9250666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets of the fusion not identified\", \"Whether all fusion partners confer similar transforming mechanisms unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"KMT2A localizes to punctate nuclear bodies; fusion proteins alter this subnuclear distribution, and partner proteins (AF4/FEL) contribute transcriptional activation domains retained in all translocation breakpoints.\",\n      \"evidence\": \"Immunocytochemistry, cell fractionation, Gal4 transactivation assays across multiple cell types\",\n      \"pmids\": [\"9041173\", \"9129043\", \"9403001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the nuclear bodies unknown\", \"In vivo relevance of altered localization not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"KMT2A fusion proteins acquire anti-apoptotic function by interacting with GADD34 and inhibiting radiation-induced apoptosis, whereas wild-type KMT2A enhances apoptosis—revealing a specific gain-of-function beyond transcriptional activation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, ionizing radiation apoptosis assays with multiple fusion constructs versus wild-type\",\n      \"pmids\": [\"10490642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GADD34 interaction is required for leukemogenesis in vivo not tested\", \"Mechanism by which fusion but not wild-type KMT2A inhibits GADD34 unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Loss-of-function studies in zebrafish demonstrated that KMT2A is required for neural progenitor proliferation and glial differentiation, extending its role beyond hematopoiesis to nervous system development.\",\n      \"evidence\": \"Morpholino knockdown and dominant-negative expression in zebrafish embryos\",\n      \"pmids\": [\"25284327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not fully excluded\", \"Target genes mediating neural phenotype not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"KMT2A's H3K4 methyltransferase activity was linked to specific transcriptional targets: it maintains NOTCH1/3 expression in glioblastoma cells and hTERT expression in melanoma, with epistasis rescue experiments placing KMT2A upstream of these pathways, and patient-derived missense variants at the CXXC and transactivation domains disrupt KMT2A target gene expression.\",\n      \"evidence\": \"KMT2A shRNA knockdown with constitutively-active NOTCH or hTERT rescue, promoter methylation analysis, xenograft models, patient fibroblast functional studies\",\n      \"pmids\": [\"28968975\", \"28726783\", \"29203834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether H3K4me3 changes are direct at all reported promoters not confirmed by ChIP in every case\", \"Generalizability of NOTCH and hTERT targets across cancer types untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"NUP98-KMT2A fusion demonstrated an alternative oncogenic mechanism—cell cycle interference and dysregulation of Sirt1/Tert/Rbl2 rather than canonical HOXA upregulation—showing that different KMT2A fusions transform through distinct transcriptional programs.\",\n      \"evidence\": \"Inducible transgenic mouse model, bone marrow repopulation, cell cycle analysis, gene expression profiling\",\n      \"pmids\": [\"31558671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NUP98-KMT2A directly occupies the dysregulated loci not shown by ChIP\", \"Relevance to human NUP98-KMT2A leukemias not validated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic epistasis in mice revealed that KMT2A and the H3K4 demethylase KDM5C functionally oppose each other at neuronal gene loci: double mutation rescues dendritic spine defects and aggression caused by single mutations, establishing a writer–eraser balance controlling neuronal chromatin.\",\n      \"evidence\": \"Single and double Kmt2a/Kdm5c knockout mice, dendritic spine morphology, behavioral assays, ChIP-seq, RNA-seq\",\n      \"pmids\": [\"32483278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific loci where writer–eraser balance is rate-limiting not fully defined\", \"Whether pharmacological modulation can recapitulate genetic rescue unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genome-wide CRISPR screens and menin inhibitor treatment revealed that menin anchors KMT2A at active enhancers; menin disruption redistributes KMT2A to bivalent promoters, derepressing polycomb-silenced genes, and identifying menin–KMT2A, MTF2–PRC2.1, and PCGF1–PRC1.1 as distinct regulators of bivalent chromatin.\",\n      \"evidence\": \"CRISPR-Cas9 screens, pharmacological menin inhibition, ChIP-seq in cancer cells and pluripotent stem cells\",\n      \"pmids\": [\"36635503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether redistribution mechanism operates identically in non-leukemic tissues unknown\", \"Structural basis for menin-dependent versus menin-independent chromatin targeting unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"KMT2A's role was extended to innate immunity: conditional knockout in monocytes/macrophages showed KMT2A drives NF-κB/RelA-dependent transcription of procoagulant factors and proinflammatory cytokines during coronavirus infection.\",\n      \"evidence\": \"Conditional Mll1 knockout in myeloid cells, murine betacoronavirus infection model, transcription assays\",\n      \"pmids\": [\"36493338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KMT2A directly deposits H3K4me3 at procoagulant gene promoters not shown by ChIP\", \"Relevance to human SARS-CoV-2 coagulopathy not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The menin–KMT2A interaction was validated as a therapeutic target: the menin inhibitor bleximenib displaces KMT2A from chromatin at MEIS1 and FLT3 loci, reducing their expression in KMT2A-rearranged and NPM1-mutant AML, supported by co-crystal structure data.\",\n      \"evidence\": \"ChIP-seq, gene expression analysis, xenograft models, co-crystal structure of menin–inhibitor complex\",\n      \"pmids\": [\"38905635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term resistance mechanisms to menin inhibition uncharacterized\", \"Whether chromatin redistribution (as per CRISPR screen findings) limits therapeutic efficacy unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"KMT2D loss in urothelium causes KMT2A–menin redistribution from KMT2D-occupied enhancers to bivalent promoters, derepressing immediate early genes—demonstrating that KMT2A chromatin occupancy is dynamically shaped by other COMPASS family members.\",\n      \"evidence\": \"Genetically engineered Kmt2c/d knockout mice, KMT2A ChIP-seq, H3K4me1/H3K27ac ChIP-seq, nascent RNA transcription assays\",\n      \"pmids\": [\"39806204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KMT2A redistribution is a general consequence of COMPASS family member loss across tissues not tested\", \"Direct structural basis for competition between KMT2A and KMT2D at shared loci unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural determinants that govern KMT2A's preference for enhancers versus bivalent promoters, how different fusion partners rewire KMT2A's chromatin targeting specificity, and whether the writer–eraser balance with KDM5C operates broadly or at select neuronal loci.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length KMT2A on chromatin\", \"Systematic comparison of chromatin occupancy across different KMT2A fusions lacking\", \"In vivo therapeutic manipulation of writer–eraser balance not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [11, 13, 14, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 10, 16]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [11, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 20]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [13, 14, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 13, 14, 17, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 9, 10, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 6, 7, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"complexes\": [\n      \"MLL1/COMPASS\",\n      \"Menin–KMT2A\"\n    ],\n    \"partners\": [\n      \"MEN1\",\n      \"KDM5C\",\n      \"ENL\",\n      \"AF4\",\n      \"AF10\",\n      \"AF9\",\n      \"GADD34\",\n      \"UNR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"KMT2A is a large histone H3 lysine 4 (H3K4) methyltransferase that functions within a multi-megadalton complex containing WDR5, RbBP5, Ash2L, menin, MOF, and HCF-1 to activate transcription at target loci including HOX genes, thereby maintaining normal hematopoiesis and neural development [PMID:12453419, PMID:15199122, PMID:16878130, PMID:15960975]. The menin–KMT2A interaction is essential both for normal HOX gene regulation and for leukemogenic transformation by KMT2A fusion oncoproteins, which retain the N-terminal AT-hook/CXXC DNA-binding domains but replace the SET domain with diverse transcriptional activation partners (ENL, AF4, AF9, AF10, ELL) that recruit DOT1L-dependent H3K79 methylation to enforce aberrant gene expression programs [PMID:16239140, PMID:21741597, PMID:9250666]. Chromosomal translocations at 11q23 creating KMT2A fusions are recurrent drivers of acute leukemia, while germline loss-of-function variants cause Wiedemann–Steiner syndrome [PMID:1423624, PMID:29203834]. Beyond hematopoiesis, KMT2A cooperates with KDM5C in an H3K4 writer–eraser balance that regulates dendritic spine morphology and behavior, and menin-dependent KMT2A redistribution maintains bivalent chromatin states at poised developmental promoters [PMID:32483278, PMID:36635503].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of KMT2A (MLL/HRX/ALL-1) as the gene spanning 11q23 breakpoints in multiple acute leukemia translocations established it as the recurrent target of these rearrangements, opening the question of what normal function is disrupted.\",\n      \"evidence\": \"YAC clone mapping and molecular cloning across t(4;11), t(6;11), t(9;11), and t(11;19) leukemias\",\n      \"pmids\": [\"1720549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No protein product or enzymatic activity characterized\", \"Normal cellular function unknown\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Cloning of the full-length KMT2A cDNA revealed it encodes a 431 kDa Drosophila trithorax homolog with AT-hook DNA-binding motifs and zinc finger domains, and that 11q23 translocations produce in-frame chimeric fusion proteins (e.g., HRX-ENL, HRX-AF4), suggesting gain-of-function oncoproteins rather than simple loss of function.\",\n      \"evidence\": \"Molecular cloning and sequence analysis of KMT2A and its fusion partners from leukemia cell lines\",\n      \"pmids\": [\"1423624\", \"1423625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"Mechanism of fusion-mediated transformation unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Expanding the repertoire of KMT2A rearrangements to include partial tandem duplications and structurally diverse fusion partners (AF10, eps15) demonstrated that the consistent retention of N-terminal DNA-binding domains is the unifying molecular feature, while partner contributions vary widely.\",\n      \"evidence\": \"Southern blot, RT-PCR, and sequence analysis across multiple leukemia subtypes and novel fusion partners\",\n      \"pmids\": [\"7662954\", \"8134107\", \"7658717\", \"8389614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What the N-terminal domains contribute molecularly beyond DNA binding\", \"Why structurally diverse partners all produce leukemia\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Functional proof that KMT2A fusions are gain-of-function oncoproteins came from retroviral transduction showing HRX-ENL immortalizes myeloid progenitors and induces leukemia in mice, with the ENL portion required; fusion partners contribute transcriptional activation domains, and wild-type KMT2A localizes to punctate nuclear bodies.\",\n      \"evidence\": \"Retroviral gene transfer, serial replating, syngeneic/SCID mouse transplantation, immunocytochemistry, and Gal4-reporter transcription assays\",\n      \"pmids\": [\"9250666\", \"9129043\", \"9403001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic activity of wild-type KMT2A protein still unknown\", \"Mechanism by which ENL contributes transformation activity unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery that KMT2A fusion proteins physically interact with GADD34 and abrogate radiation-induced apoptosis—while wild-type KMT2A promotes it—established anti-apoptotic gain-of-function as a second oncogenic mechanism beyond proliferation/immortalization.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and apoptosis assays with three different fusion proteins versus wild-type\",\n      \"pmids\": [\"10490642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GADD34 interaction is required for leukemogenesis in vivo\", \"How wild-type KMT2A promotes apoptosis molecularly\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Biochemical purification revealed KMT2A assembles a >1 MDa supercomplex with histone-modifying and chromatin-remodeling activities, and its SET domain directly methylates H3K4 at target loci including Hoxa9, finally establishing KMT2A as a histone methyltransferase.\",\n      \"evidence\": \"Biochemical purification, mass spectrometry, histone methyltransferase assays, and ChIP at Hoxa9\",\n      \"pmids\": [\"12453419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Minimal complex required for catalytic activity not defined\", \"Whether SET domain loss in fusion proteins is sufficient for transformation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of menin as a stoichiometric KMT2A complex subunit, and demonstration that menin loss phenocopies KMT2A loss for HOX gene expression, established the menin–KMT2A interaction as essential for normal complex function.\",\n      \"evidence\": \"Biochemical purification, co-immunoprecipitation, RNAi knockdown, and gene expression analysis\",\n      \"pmids\": [\"15199122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether menin is also required for oncogenic KMT2A fusions (answered the next year)\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Three key advances defined the architecture and regulation of the KMT2A complex: WDR5 reads H3K4me2 to present substrate, MOF couples H4K16 acetylation with H3K4 methylation for transcriptional activation, and menin is an essential oncogenic cofactor whose ablation reverses HOX dysregulation and differentiation arrest in KMT2A-fusion leukemia.\",\n      \"evidence\": \"Reconstituted in vitro chromatin transcription, nucleosome binding assays, conditional genetic ablation, and ChIP\",\n      \"pmids\": [\"15960974\", \"15960975\", \"16239140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of menin–KMT2A interaction at atomic resolution\", \"Whether menin inhibition is therapeutically feasible\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Biochemical reconstitution of the minimal four-subunit core complex (MLL1-SET/WDR5/RbBP5/Ash2L) defined the catalytic module and showed WDR5 bridges enzyme and substrate, establishing the structural framework for the SET1-family methyltransferases.\",\n      \"evidence\": \"Reconstitution with purified recombinant proteins, in vitro HMT assay, crystal structure of WDR5\",\n      \"pmids\": [\"16878130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length complex structure not determined\", \"Regulation of processivity (mono- vs. di- vs. trimethylation) unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genome-wide epigenetic profiling resolved how KMT2A fusions activate transcription without H3K4 methyltransferase activity: MLL-AF9 fusion recruits DOT1L to deposit aberrant H3K79me2 at target loci, and DOT1L inactivation selectively suppresses fusion-driven leukemia, identifying DOT1L as the critical downstream effector.\",\n      \"evidence\": \"ChIP-seq for multiple histone marks, genetic Dot1l inactivation, gene expression profiling, in vivo leukemia model\",\n      \"pmids\": [\"21741597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all KMT2A fusion partners converge on DOT1L recruitment\", \"Therapeutic window for DOT1L inhibition in patients\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Germline loss-of-function KMT2A variants (splice, CXXC domain, transactivation domain) cause Wiedemann–Steiner syndrome with domain-specific molecular consequences, establishing KMT2A haploinsufficiency as a Mendelian developmental disorder mechanism.\",\n      \"evidence\": \"Splice assays, Western blot, qRT-PCR of target genes, and subcellular localization in patient fibroblasts\",\n      \"pmids\": [\"29203834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype–phenotype correlations across the full WSS mutation spectrum incomplete\", \"Tissue-specific consequences of individual domain mutations not explored in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic epistasis between Kmt2a and the H3K4 demethylase Kdm5c established that KMT2A operates in a writer–eraser balance critical for dendritic spine morphology and behavior, extending its role beyond hematopoiesis to neuronal function.\",\n      \"evidence\": \"Single and double knockout mouse models with dendritic morphology, behavioral, transcriptomic, and H3K4me profiling\",\n      \"pmids\": [\"32483278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific neuronal target genes require the KMT2A–KDM5C balance\", \"Whether this mechanism operates in human neurodevelopmental disease\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genome-wide CRISPR screens and ChIP-seq revealed that menin–KMT2A complexes maintain bivalent chromatin at developmental promoters; menin loss or pharmacological inhibition paradoxically derepresses bivalent genes by redistributing KMT2A, uncovering a mechanism by which menin inhibitors may have unintended activating effects beyond target gene silencing.\",\n      \"evidence\": \"Whole-genome CRISPR-Cas9 screens, pharmacological menin inhibition, ChIP-seq across cancer cells and pluripotent stem cells\",\n      \"pmids\": [\"36635503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term consequences of bivalent gene derepression during menin inhibitor therapy\", \"Whether KMT2A redistribution varies across tissue types\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss of KMT2C/D in urothelium causes compensatory redistribution of KMT2A–menin to CpG-high and bivalent promoters, derepressing immediate early genes and impairing differentiation, revealing inter-family crosstalk among KMT2 paralogs that creates therapeutic vulnerability to EGFR inhibition.\",\n      \"evidence\": \"Kmt2c/d knockout mouse models, KMT2A/menin ChIP-seq, nascent RNA transcription assays, EGFR inhibitor testing\",\n      \"pmids\": [\"39806204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether paralog redistribution occurs in other epithelial cancers with KMT2C/D loss\", \"Structural basis for preferential KMT2A targeting to CpG-rich promoters\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the atomic-resolution structure of the full-length KMT2A complex with menin and chromatin, the deterministic rules governing KMT2A mono- versus di- versus trimethylation processivity, and the long-term clinical consequences of menin inhibitor–induced KMT2A redistribution to bivalent promoters.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length KMT2A–menin–nucleosome cryo-EM structure\", \"Processivity regulation by complex composition incompletely defined\", \"Clinical impact of bivalent gene derepression during menin inhibitor therapy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [12, 14, 15, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12, 14, 16, 18, 27]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12, 15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [12, 15, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 14, 15, 17, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [12, 14, 16, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 21, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 16, 19, 26]}\n    ],\n    \"complexes\": [\n      \"MLL1/COMPASS-like complex (MLL1-SET/WDR5/RbBP5/Ash2L)\",\n      \"MLL1-MOF complex\",\n      \"Menin-KMT2A complex\"\n    ],\n    \"partners\": [\n      \"WDR5\",\n      \"RBBP5\",\n      \"ASH2L\",\n      \"MEN1\",\n      \"KAT8\",\n      \"HCFC1\",\n      \"DOT1L\",\n      \"CSDE1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}