{"gene":"KMT2A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1997,"finding":"HRX-ENL fusion protein immortalizes myelomonocytic precursors and induces myeloid leukemia in vivo; a deletion mutant of HRX-ENL lacking the ENL component failed to transform, demonstrating that the ENL portion is required for oncogenic gain-of-function.","method":"Retroviral gene transfer into hematopoietic stem cells, in vitro colony replating assays, transplantation into syngeneic and SCID mice","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function deletion mutant with defined cellular phenotype, confirmed in vivo leukemia induction, replicated across multiple assays in one rigorous study","pmids":["9250666"],"is_preprint":false},{"year":1998,"finding":"Oncogenic activity of HRX-ENL requires: (1) the AT-hook motifs of HRX for DNA binding, (2) the methyltransferase homology domain of HRX (shown to bind DNA non-sequence-specifically in vitro), and (3) the C-terminal 84 amino acids of ENL which are necessary and sufficient for transcriptional activation and correlate with transforming activity.","method":"Structure-function deletion analysis, in vitro myeloid immortalization assay, in vitro DNA-binding assay, transcriptional transactivation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple deletion mutants with defined functional readouts, in vitro biochemical assay for DNA binding, transcriptional activation correlated with transformation","pmids":["9418860"],"is_preprint":false},{"year":1994,"finding":"In t(4;11) leukemias, HRX is fused in-frame to FEL (AF-4), a serine/proline-rich protein; the fusion places 913 C-terminal amino acids of FEL onto the N-terminal portion of HRX containing its AT-hook DNA-binding motifs.","method":"cDNA cloning, Northern blot, sequence analysis of fusion transcripts","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — molecular cloning and sequence characterization replicated in multiple leukemia cases, but purely molecular/structural without functional reconstitution","pmids":["8443374"],"is_preprint":false},{"year":1994,"finding":"ENL, the t(11;19) fusion partner of HRX, is a nuclear protein with intrinsic transcriptional activation activity in both lymphoid and myeloid cells; the minimal transactivation domain maps to the C-terminal 90 amino acids, which are also conserved in AF-9 and retained in all HRX-ENL fusion proteins.","method":"Deletion mutagenesis, transcriptional reporter assays in lymphoid cells, myeloid cells, and yeast","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transactivation assays with deletion mutagenesis, multiple cell types tested, domain mapped precisely","pmids":["8080983"],"is_preprint":false},{"year":1999,"finding":"HRX proteins interact directly with GADD34; three different HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) inhibit GADD34-induced apoptosis after ionizing radiation, whereas wild-type HRX enhances apoptosis. GADD34 also binds hSNF5/INI1, a chromatin-remodeling complex subunit.","method":"Yeast two-hybrid, co-immunoprecipitation from human cells, overexpression apoptosis assays with ionizing radiation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus reciprocal co-IP confirmed interaction; functional apoptosis assay with three different fusion proteins versus wild-type in the same study","pmids":["10490642"],"is_preprint":false},{"year":1997,"finding":"A region of HRX consistently retained in leukemic fusion proteins interacts directly with SET (a leukemia-associated protein) near the AT-hook domains; a single amino acid mutation in the SET-binding site reduces both co-immunoprecipitated SET and co-immunoprecipitated protein phosphatase 2A (PP2A), indicating HRX forms a heterocomplex with SET and PP2A.","method":"Yeast two-hybrid, in vitro binding studies, co-immunoprecipitation, site-directed mutagenesis, phosphatase activity assay with okadaic acid","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid plus in vitro binding plus co-IP plus mutagenesis; single lab but multiple orthogonal methods","pmids":["9353299"],"is_preprint":false},{"year":1997,"finding":"Wild-type HRX/ALL-1 protein localizes to nuclear structures in a punctate distribution, whereas the HRX/ALL-1-eps15 fusion protein localizes exclusively to the nucleus in bodies that are smaller and more numerous, indicating fusion with eps15 alters the subcellular compartmentalization of HRX.","method":"Immunocytochemistry with polyclonal and monoclonal antibodies; Western blot of cells with 11q23 translocations; transfection with HRX-ENL fusion gene for antibody validation","journal":"Blood / Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunolocalization in multiple cell types; two independent papers (PMID 9129043 and 9041173) showing nuclear localization; functional consequence of altered localization inferred but not directly tested","pmids":["9129043","9041173"],"is_preprint":false},{"year":1997,"finding":"The FEL (AF-4) protein donates transcriptional activation sequences to HRX-FEL fusion proteins; the transactivating region maps to amino acids 365–572 of FEL, which is consistently retained in HRX-FEL fusions created by t(4;11) translocations.","method":"Gal4-fusion transcriptional reporter assays in multiple cell lines","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transactivation assay with deletion mapping; single lab, one method but multiple cell types","pmids":["9403001"],"is_preprint":false},{"year":1996,"finding":"The N-terminal segment of ALL-1 interacts with UNR, a protein containing multiple cold shock domains (CSD); the minimal region of UNR required includes two CSD and two intervening polypeptides. Interaction confirmed by in vitro binding and co-immunoprecipitation from COS cells.","method":"Yeast two-hybrid screening, in vitro binding studies, co-immunoprecipitation from COS cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast two-hybrid plus in vitro binding plus co-IP; single lab but three orthogonal methods","pmids":["8934551"],"is_preprint":false},{"year":1997,"finding":"The ALL-1 protein is predominantly localized in the nucleus; recombinant AT-hook and zinc-binding subdomains of ALL-1 interact in vitro with double-stranded oligodeoxynucleotides, supporting both sequence-unspecific (AT-hook) and sequence-specific (zinc-binding) DNA-binding modes.","method":"Anti-ALL-1 antisera immunolocalization, Western blot, in vitro DNA-binding assay with recombinant protein subdomains","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro DNA binding assay plus nuclear localization by immunostaining; single lab","pmids":["9158002"],"is_preprint":false},{"year":2017,"finding":"KMT2A (H3K4 methyltransferase) controls largely distinct genomic regions and molecular pathways from KMT2B in hippocampal neurons; Kmt2a knockdown decreases H3K4 methylation at specific loci and impairs memory formation in mice.","method":"Mouse knockdown model, H3K4 methylation ChIP analysis, gene expression profiling, behavioral memory tests","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined epigenomic and behavioral phenotype; single lab","pmids":["28723559"],"is_preprint":false},{"year":2020,"finding":"KMT2A and the H3K4 demethylase KDM5C have mutually suppressive roles; double mutation of Kmt2a and Kdm5c in mice reverses dendritic spine deficits, behavioral traits including aggression, and partially corrects altered H3K4 methylation landscapes seen in each single mutant.","method":"Double-mutant mouse models, dendritic spine morphology, behavioral tests, H3K4me ChIP-seq, RNA-seq","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double mutant rescue, multiple orthogonal readouts (epigenomic, morphological, behavioral)","pmids":["32483278"],"is_preprint":false},{"year":2023,"finding":"Menin-KMT2A interaction is a critical transcriptional dependency in KMT2A-rearranged and NPM1-mutant acute leukemia; pharmacological inhibition of menin-KMT2A interaction with revumenib induces leukemic differentiation and achieves remission in patients, establishing the menin–KMT2A protein–protein interaction as the functional oncogenic dependency.","method":"First-in-human phase 1 clinical trial with mechanistic correlatives (differentiation markers, residual disease clearance); prior preclinical menin-KMT2A inhibitor studies established the interaction","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clinical proof-of-concept with mechanistic differentiation syndrome correlate; independently replicated across multiple trials (PMID 36922593, 39121437)","pmids":["36922593","39121437"],"is_preprint":false},{"year":2023,"finding":"Menin inhibition (loss of menin-KMT2A/B complex) paradoxically derepresses bivalent genes by redistributing KMT2A from active genes to bivalent promoters; a Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent loci.","method":"Genome-wide CRISPR-Cas9 screens, pharmacological menin inhibition, H3K4me3/H3K27me3 ChIP-seq, genetic knockout in cancer cells and pluripotent stem cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screens plus ChIP-seq with multiple genetic and pharmacological perturbations; mechanistic distinction between Menin-dependent and independent KMT2A functions","pmids":["36635503"],"is_preprint":false},{"year":2024,"finding":"JNJ-75276617 (bleximenib) inhibits the menin-KMT2A protein-protein interaction; a co-crystal structure of menin with JNJ-75276617 reveals a binding mode distinct from revumenib. Inhibition displaces the menin-KMT2A complex from target gene promoters (including MEIS1 and FLT3), reducing their expression.","method":"Co-crystal structure determination, chromatin immunoprecipitation-seq, gene expression analysis, in vitro antiproliferative assays, xenograft models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus ChIP-seq plus functional validation in vitro and in vivo in a single study","pmids":["38905635"],"is_preprint":false},{"year":2019,"finding":"KMT2A promotes colorectal cancer invasion and metastasis by transcriptionally activating cathepsin Z (CTSZ); p65 (NF-κB) recruits KMT2A to the CTSZ promoter, and knockdown of p65 reduces KMT2A occupancy at the CTSZ promoter.","method":"KMT2A knockdown in HCT116/DLD1 cells, in vivo xenograft metastasis model, ChIP assay showing p65 recruits KMT2A to CTSZ promoter","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP confirming promoter occupancy, KD with defined metastasis phenotype; single lab","pmids":["31090199"],"is_preprint":false},{"year":2017,"finding":"KMT2A promotes melanoma cell growth by activating hTERT transcription; KMT2A knockdown reduces hTERT promoter activity and expression, and hTERT overexpression rescues the proliferation defect caused by KMT2A knockdown.","method":"KMT2A knockdown/overexpression in melanoma cell lines, hTERT promoter reporter assay, rescue experiment with hTERT overexpression, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — promoter reporter plus genetic rescue experiment plus in vivo validation; single lab","pmids":["28726783"],"is_preprint":false},{"year":2023,"finding":"KMT2A promotes monocyte/macrophage expression of procoagulant (tissue factor, F3) and profibrinolytic factors (PLAU, PLAUR) and proinflammatory cytokines through NF-κB/RelA-dependent transcription; MLL1-dependent phenotypes were confirmed in a coronavirus infection model in vivo.","method":"Conditional MLL1 knockout in monocytes/macrophages using murine betacoronavirus MHVA59 model, in vitro NF-κB reporter assays, in vivo coagulation phenotype measurements, analysis of human SARS-CoV-2 positive samples","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with defined coagulation phenotype plus in vitro mechanistic NF-κB pathway placement; single lab but multiple orthogonal approaches","pmids":["36493338"],"is_preprint":false},{"year":2024,"finding":"KMT2A promotes expression of METTL3 via H3K4me3 modification; METTL3-mediated m6A modification then reduces ATG4a RNA stability, impairing autophagy in nucleus pulposus cells, which drives GATA4-dependent senescence and intervertebral disc degeneration.","method":"KMT2A and METTL3 silencing in nucleus pulposus cells, ChIP for H3K4me3 at METTL3 promoter, m6A-seq/MeRIP, ATG4a RNA stability assay, autophagic flux measurement, SASP quantification","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming H3K4me3 at METTL3 promoter, m6A modification assay, RNA stability readout; single lab with multiple orthogonal methods","pmids":["39572532"],"is_preprint":false},{"year":2024,"finding":"An enhancer-derived lncRNA (Myrlin) physically interacts with the KMT2A/MLL1 complex and recruits it to the Myb locus; Myrlin CRISPRi reduces KMT2A occupancy at Myb, decreasing CDK9 and RNA Pol II binding and causing Pol II pausing in the Myb first exon/intron.","method":"CRISPR-Cas9 TSS deletion, CRISPRi, RNA immunoprecipitation showing Myrlin-KMT2A interaction, ChIP for KMT2A/CDK9/Pol II at Myb locus, 3C/chromosome conformation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP confirming interaction, ChIP showing loss of KMT2A occupancy upon Myrlin loss, genetic perturbations with defined transcriptional phenotype; single lab","pmids":["38889007"],"is_preprint":false},{"year":2025,"finding":"Loss of KMT2C/D in urothelium causes KMT2A-menin complex to redistribute from KMT2D-occupied enhancers to CpG-high and bivalent promoters, derepressing signal-induced immediate early genes; KMT2A-menin redistribution is a mechanistic consequence of KMT2C/D loss.","method":"Genetically engineered mouse models (Kmt2c/d knockout), ChIP-seq for KMT2A, H3K4me1, H3K27ac, nascent RNA transcription assays, functional differentiation and transformation assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with genome-wide ChIP-seq demonstrating KMT2A redistribution; multiple orthogonal epigenomic readouts","pmids":["39806204"],"is_preprint":false},{"year":2017,"finding":"KMT2A missense variant p.Arg1154Trp (in the CXXC domain) causes disturbed subcellular distribution of KMT2A and alters expression of KMT2A target genes in patient fibroblasts; a variant in the transactivation domain (p.Met2853Arg) also alters target gene expression without affecting localization, demonstrating that both domains are functionally critical.","method":"Primary patient fibroblasts, immunofluorescence for subcellular localization, qRT-PCR for target gene expression","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — direct localization experiment with functional consequence in patient cells; single lab, limited to two variants","pmids":["29203834"],"is_preprint":false},{"year":2023,"finding":"Proteasome inhibition in KMT2A-rearranged infant ALL depletes histone H2B monoubiquitination (H2Bub1) and histone H3K79 dimethylation at KMT2A target genes and downregulates the KMT2A gene expression signature, indicating proteasome inhibitors target the KMT2A transcriptional complex.","method":"Drug screen in primary KMT2Ar infant ALL specimens, ChIP analysis of H2Bub1 and H3K79me2, KMT2A target gene expression profiling","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP demonstrating loss of KMT2A-associated histone marks at target genes; single lab, primary patient specimens","pmids":["36781850"],"is_preprint":false}],"current_model":"KMT2A (MLL1/HRX/ALL-1) is a nuclear H3K4 methyltransferase that binds DNA through AT-hook and CXXC domains, forms a menin-dependent complex that deposits activating H3K4me3 at target gene promoters (including HOXA genes, MEIS1, FLT3, hTERT, and CTSZ), maintains bivalent chromatin by opposing polycomb-mediated repression at developmental loci, recruits NF-κB/RelA for inflammatory gene transcription, and is converted to a gain-of-function oncogenic transcription factor in leukemia by chromosomal translocations that fuse its N-terminal DNA-binding region to partner proteins (ENL, AF-4/FEL, AF-9, AF-10, ELL) that contribute transcriptional activation domains, while also interacting with SET/PP2A and GADD34 complexes; disruption of the menin–KMT2A protein–protein interaction with small-molecule inhibitors (revumenib, bleximenib) displaces the complex from chromatin, downregulates target genes, and induces leukemic differentiation."},"narrative":{"mechanistic_narrative":"KMT2A (MLL1/HRX/ALL-1) is a nuclear histone H3K4 methyltransferase that binds DNA and deposits activating H3K4me3 to control developmental and signal-responsive gene programs [PMID:9158002, PMID:36635503]. It engages chromatin through its own DNA-binding modules: recombinant AT-hook subdomains bind double-stranded DNA non-sequence-specifically while a zinc-binding (CXXC) subdomain supports sequence-specific binding, and a CXXC-domain missense variant disturbs KMT2A subcellular distribution and target-gene expression in patient cells [PMID:9158002, PMID:29203834]. A menin-dependent KMT2A complex occupies active gene promoters; loss of the menin interaction redistributes KMT2A to bivalent promoters, revealing a menin-independent function in maintaining H3K4me3 and opposing polycomb-mediated repression, and loss of KMT2C/D similarly redirects the KMT2A-menin complex from enhancers to CpG-high and bivalent promoters [PMID:36635503, PMID:39806204]. KMT2A is recruited to specific targets by partner factors — NF-κB/RelA (p65) brings it to the CTSZ promoter to drive colorectal invasion and to procoagulant/proinflammatory loci in monocytes/macrophages, while an enhancer-derived lncRNA (Myrlin) recruits the KMT2A complex to the Myb locus to license productive RNA Pol II elongation [PMID:31090199, PMID:36493338, PMID:38889007]. Through these target programs KMT2A activates transcription of genes including hTERT in melanoma and METTL3 in nucleus pulposus cells, and in hippocampal neurons it deposits locus-specific H3K4 methylation required for memory, acting in mutual antagonism with the demethylase KDM5C [PMID:28726783, PMID:39572532, PMID:28723559, PMID:32483278]. In leukemia, chromosomal translocations fuse the N-terminal AT-hook/DNA-binding region of KMT2A to partner proteins (ENL, AF-4/FEL, AF-9, AF-10, ELL) that donate transcriptional activation domains, converting it into a gain-of-function oncogenic transcription factor; the ENL C-terminal ~84–90 residues are necessary and sufficient for both transactivation and transformation, and AT-hook DNA binding plus the methyltransferase-homology domain are required for the oncogenic activity [PMID:9250666, PMID:9418860, PMID:8080983, PMID:9403001]. The menin–KMT2A protein–protein interaction is the functional oncogenic dependency: small-molecule inhibitors (revumenib, bleximenib) displace the complex from target promoters such as MEIS1 and FLT3, downregulate the KMT2A signature, and induce leukemic differentiation and clinical remission [PMID:36922593, PMID:39121437, PMID:38905635].","teleology":[{"year":1994,"claim":"Established the molecular architecture of the leukemic fusions, showing that translocation partners (FEL/AF-4, ENL) are joined in-frame to the N-terminal AT-hook-containing portion of KMT2A and that the partners carry intrinsic transcriptional activation domains.","evidence":"cDNA cloning and sequencing of t(4;11) fusion transcripts; deletion mutagenesis and transcriptional reporter assays for ENL across lymphoid, myeloid, and yeast systems","pmids":["8443374","8080983"],"confidence":"Medium","gaps":["No functional reconstitution of the FEL fusion's transforming activity in these studies","Mechanism by which the partner activation domain reprograms KMT2A targets not defined"]},{"year":1996,"claim":"Identified early physical partners of the KMT2A N-terminus (UNR, with cold-shock domains), beginning the mapping of its protein interaction network.","evidence":"Yeast two-hybrid screen, in vitro binding, and co-IP from COS cells","pmids":["8934551"],"confidence":"Medium","gaps":["Functional consequence of the UNR interaction not established","Single-lab interaction without in vivo validation"]},{"year":1997,"claim":"Defined how KMT2A engages chromatin and assembles regulatory heterocomplexes, showing AT-hook and zinc-binding DNA-binding modes, nuclear punctate localization, and direct association with the SET–PP2A complex.","evidence":"Recombinant subdomain DNA-binding assays, immunolocalization, yeast two-hybrid, co-IP, and site-directed mutagenesis with phosphatase activity readout","pmids":["9158002","9129043","9041173","9353299","9403001"],"confidence":"Medium","gaps":["Sequence-specific DNA targets in vivo not identified","Role of the SET–PP2A heterocomplex in normal KMT2A function unresolved"]},{"year":1998,"claim":"Dissected the gain-of-function requirements of an MLL fusion, showing transformation requires KMT2A AT-hooks and methyltransferase-homology domain plus the partner's transactivation domain, directly linking transactivation to oncogenesis.","evidence":"Structure-function deletion analysis with in vitro myeloid immortalization, DNA-binding, and transactivation assays; in vivo leukemia induction by HRX-ENL","pmids":["9418860","9250666"],"confidence":"High","gaps":["Did not identify the chromatin targets responsible for transformation","Mechanistic link between DNA binding and aberrant transcription not resolved at the gene level"]},{"year":1999,"claim":"Connected KMT2A and its fusions to apoptotic control, showing wild-type KMT2A enhances GADD34-induced apoptosis while fusions inhibit it.","evidence":"Yeast two-hybrid, reciprocal co-IP, and overexpression apoptosis assays after ionizing radiation with three fusion proteins versus wild-type","pmids":["10490642"],"confidence":"High","gaps":["Physiological relevance of the GADD34 axis to leukemogenesis not demonstrated in vivo","Link to KMT2A's methyltransferase activity unexplored"]},{"year":2017,"claim":"Extended KMT2A function beyond leukemia, showing locus-specific H3K4 methylation roles in neuronal memory and oncogenic activation of hTERT in melanoma.","evidence":"Mouse Kmt2a knockdown with H3K4me ChIP and memory behavior; melanoma KMT2A knockdown/overexpression with hTERT promoter reporter and rescue","pmids":["28723559","28726783"],"confidence":"Medium","gaps":["Recruitment mechanism to neuronal and hTERT loci not defined","Single-lab studies"]},{"year":2019,"claim":"Identified a recruitment logic for non-leukemic KMT2A targeting, showing NF-κB/p65 recruits KMT2A to the CTSZ promoter to drive metastasis.","evidence":"KMT2A knockdown in colorectal cells, xenograft metastasis model, and ChIP showing p65-dependent KMT2A occupancy","pmids":["31090199"],"confidence":"Medium","gaps":["Direct p65–KMT2A physical interaction not biochemically resolved","Generality of p65-directed recruitment beyond CTSZ untested here"]},{"year":2020,"claim":"Defined a chromatin balance principle, showing KMT2A and the demethylase KDM5C act in mutual antagonism such that combined loss rescues single-mutant epigenomic and behavioral defects.","evidence":"Double-mutant mouse genetics with dendritic spine, behavioral, H3K4me ChIP-seq, and RNA-seq readouts","pmids":["32483278"],"confidence":"Medium","gaps":["Whether antagonism is direct or via shared targets not resolved","Restricted to neuronal context"]},{"year":2023,"claim":"Established the menin–KMT2A interaction as the therapeutic oncogenic dependency and distinguished menin-dependent active-gene occupancy from a menin-independent bivalent-gene function.","evidence":"First-in-human revumenib trial with differentiation correlatives; genome-wide CRISPR screens and H3K4me3/H3K27me3 ChIP-seq with genetic and pharmacological menin perturbation","pmids":["36922593","39121437","36635503"],"confidence":"High","gaps":["Molecular basis of menin-independent bivalent maintenance not fully defined","Determinants of redistribution between active and bivalent loci unresolved"]},{"year":2023,"claim":"Linked KMT2A to inflammatory/coagulation transcription and to histone-mark dependencies, placing it downstream of NF-κB/RelA in macrophages and within a proteasome-sensitive H2Bub1/H3K79me2 axis in KMT2A-rearranged ALL.","evidence":"Conditional MLL1 macrophage knockout in a coronavirus model with NF-κB reporters; drug screen in primary KMT2Ar infant ALL with H2Bub1/H3K79me2 ChIP and signature profiling","pmids":["36493338","36781850"],"confidence":"Medium","gaps":["Direct KMT2A–RelA biochemical interaction not mapped","Mechanism linking proteasome activity to histone marks at KMT2A targets indirect"]},{"year":2024,"claim":"Resolved the structural basis and target consequences of menin–KMT2A inhibition and identified RNA-guided recruitment, showing bleximenib's distinct binding mode displaces the complex from MEIS1/FLT3 and that lncRNA Myrlin recruits KMT2A to license Myb elongation.","evidence":"Menin–inhibitor co-crystal structure with ChIP-seq and xenograft validation; RNA-IP, ChIP, and 3C at the Myb locus with CRISPRi","pmids":["38905635","38889007"],"confidence":"Medium","gaps":["Generality of lncRNA-mediated recruitment across loci unknown","How KMT2A occupancy controls Pol II pause release mechanistically incomplete"]},{"year":2025,"claim":"Showed that KMT2A genomic positioning is dictated by sister methyltransferases, with KMT2C/D loss redistributing the KMT2A-menin complex from enhancers to bivalent/CpG-high promoters and derepressing immediate-early genes.","evidence":"Kmt2c/d knockout mouse models with KMT2A, H3K4me1, H3K27ac ChIP-seq and nascent transcription assays","pmids":["39806204"],"confidence":"High","gaps":["Whether redistribution is competitive or signal-dependent not fully resolved","Consequences for human tumors beyond urothelium untested here"]},{"year":null,"claim":"How KMT2A's catalytic H3K4 methyltransferase activity is mechanistically coupled to its diverse recruitment routes (NF-κB, lncRNAs, menin, sister KMTs) and how this determines locus-specific outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how recruitment factors select between active and bivalent targets","Direct in vivo structure of the assembled KMT2A complex on chromatin not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[13,18,22]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,7,15,16]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[10,13,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,9,21]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13,20,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[15,16,17,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,12,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17]}],"complexes":["menin-KMT2A complex","SET-PP2A heterocomplex"],"partners":["MEN1","ENL","AFF1","GADD34","SET","PP2A","RELA","CSDE1"],"other_free_text":[]}},"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 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bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37036970","citation_count":13,"is_preprint":false},{"pmid":"38554812","id":"PMC_38554812","title":"Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38554812","citation_count":13,"is_preprint":false},{"pmid":"9403001","id":"PMC_9403001","title":"The FEL (AF-4) protein donates transcriptional activation sequences to Hrx-Fel fusion proteins in leukemias containing T(4;11)(Q21;Q23) chromosomal translocations.","date":"1997","source":"Leukemia 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Leukemia.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38730645","citation_count":12,"is_preprint":false},{"pmid":"36737785","id":"PMC_36737785","title":"Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway.","date":"2023","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/36737785","citation_count":12,"is_preprint":false},{"pmid":"36591284","id":"PMC_36591284","title":"Expression of TRX1 optimizes the antitumor functions of human CAR T cells and confers resistance to a pro-oxidative tumor microenvironment.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36591284","citation_count":12,"is_preprint":false},{"pmid":"32437908","id":"PMC_32437908","title":"Epigenetic regulation of protein translation in KMT2A-rearranged AML.","date":"2020","source":"Experimental 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674872","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53749,"output_tokens":5741,"usd":0.123681,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14250,"output_tokens":4804,"usd":0.095675,"stage2_stop_reason":"end_turn"},"total_usd":0.219356,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"HRX-ENL fusion protein immortalizes myelomonocytic precursors and induces myeloid leukemia in vivo; a deletion mutant of HRX-ENL lacking the ENL component failed to transform, demonstrating that the ENL portion is required for oncogenic gain-of-function.\",\n      \"method\": \"Retroviral gene transfer into hematopoietic stem cells, in vitro colony replating assays, transplantation into syngeneic and SCID mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function deletion mutant with defined cellular phenotype, confirmed in vivo leukemia induction, replicated across multiple assays in one rigorous study\",\n      \"pmids\": [\"9250666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Oncogenic activity of HRX-ENL requires: (1) the AT-hook motifs of HRX for DNA binding, (2) the methyltransferase homology domain of HRX (shown to bind DNA non-sequence-specifically in vitro), and (3) the C-terminal 84 amino acids of ENL which are necessary and sufficient for transcriptional activation and correlate with transforming activity.\",\n      \"method\": \"Structure-function deletion analysis, in vitro myeloid immortalization assay, in vitro DNA-binding assay, transcriptional transactivation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple deletion mutants with defined functional readouts, in vitro biochemical assay for DNA binding, transcriptional activation correlated with transformation\",\n      \"pmids\": [\"9418860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"In t(4;11) leukemias, HRX is fused in-frame to FEL (AF-4), a serine/proline-rich protein; the fusion places 913 C-terminal amino acids of FEL onto the N-terminal portion of HRX containing its AT-hook DNA-binding motifs.\",\n      \"method\": \"cDNA cloning, Northern blot, sequence analysis of fusion transcripts\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — molecular cloning and sequence characterization replicated in multiple leukemia cases, but purely molecular/structural without functional reconstitution\",\n      \"pmids\": [\"8443374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"ENL, the t(11;19) fusion partner of HRX, is a nuclear protein with intrinsic transcriptional activation activity in both lymphoid and myeloid cells; the minimal transactivation domain maps to the C-terminal 90 amino acids, which are also conserved in AF-9 and retained in all HRX-ENL fusion proteins.\",\n      \"method\": \"Deletion mutagenesis, transcriptional reporter assays in lymphoid cells, myeloid cells, and yeast\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transactivation assays with deletion mutagenesis, multiple cell types tested, domain mapped precisely\",\n      \"pmids\": [\"8080983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HRX proteins interact directly with GADD34; three different HRX fusion proteins (HRX-ENL, HRX-AF9, HRX-ELL) inhibit GADD34-induced apoptosis after ionizing radiation, whereas wild-type HRX enhances apoptosis. GADD34 also binds hSNF5/INI1, a chromatin-remodeling complex subunit.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from human cells, overexpression apoptosis assays with ionizing radiation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus reciprocal co-IP confirmed interaction; functional apoptosis assay with three different fusion proteins versus wild-type in the same study\",\n      \"pmids\": [\"10490642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A region of HRX consistently retained in leukemic fusion proteins interacts directly with SET (a leukemia-associated protein) near the AT-hook domains; a single amino acid mutation in the SET-binding site reduces both co-immunoprecipitated SET and co-immunoprecipitated protein phosphatase 2A (PP2A), indicating HRX forms a heterocomplex with SET and PP2A.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding studies, co-immunoprecipitation, site-directed mutagenesis, phosphatase activity assay with okadaic acid\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid plus in vitro binding plus co-IP plus mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9353299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Wild-type HRX/ALL-1 protein localizes to nuclear structures in a punctate distribution, whereas the HRX/ALL-1-eps15 fusion protein localizes exclusively to the nucleus in bodies that are smaller and more numerous, indicating fusion with eps15 alters the subcellular compartmentalization of HRX.\",\n      \"method\": \"Immunocytochemistry with polyclonal and monoclonal antibodies; Western blot of cells with 11q23 translocations; transfection with HRX-ENL fusion gene for antibody validation\",\n      \"journal\": \"Blood / Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunolocalization in multiple cell types; two independent papers (PMID 9129043 and 9041173) showing nuclear localization; functional consequence of altered localization inferred but not directly tested\",\n      \"pmids\": [\"9129043\", \"9041173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The FEL (AF-4) protein donates transcriptional activation sequences to HRX-FEL fusion proteins; the transactivating region maps to amino acids 365–572 of FEL, which is consistently retained in HRX-FEL fusions created by t(4;11) translocations.\",\n      \"method\": \"Gal4-fusion transcriptional reporter assays in multiple cell lines\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transactivation assay with deletion mapping; single lab, one method but multiple cell types\",\n      \"pmids\": [\"9403001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The N-terminal segment of ALL-1 interacts with UNR, a protein containing multiple cold shock domains (CSD); the minimal region of UNR required includes two CSD and two intervening polypeptides. Interaction confirmed by in vitro binding and co-immunoprecipitation from COS cells.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro binding studies, co-immunoprecipitation from COS cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast two-hybrid plus in vitro binding plus co-IP; single lab but three orthogonal methods\",\n      \"pmids\": [\"8934551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The ALL-1 protein is predominantly localized in the nucleus; recombinant AT-hook and zinc-binding subdomains of ALL-1 interact in vitro with double-stranded oligodeoxynucleotides, supporting both sequence-unspecific (AT-hook) and sequence-specific (zinc-binding) DNA-binding modes.\",\n      \"method\": \"Anti-ALL-1 antisera immunolocalization, Western blot, in vitro DNA-binding assay with recombinant protein subdomains\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro DNA binding assay plus nuclear localization by immunostaining; single lab\",\n      \"pmids\": [\"9158002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A (H3K4 methyltransferase) controls largely distinct genomic regions and molecular pathways from KMT2B in hippocampal neurons; Kmt2a knockdown decreases H3K4 methylation at specific loci and impairs memory formation in mice.\",\n      \"method\": \"Mouse knockdown model, H3K4 methylation ChIP analysis, gene expression profiling, behavioral memory tests\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined epigenomic and behavioral phenotype; single lab\",\n      \"pmids\": [\"28723559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KMT2A and the H3K4 demethylase KDM5C have mutually suppressive roles; double mutation of Kmt2a and Kdm5c in mice reverses dendritic spine deficits, behavioral traits including aggression, and partially corrects altered H3K4 methylation landscapes seen in each single mutant.\",\n      \"method\": \"Double-mutant mouse models, dendritic spine morphology, behavioral tests, H3K4me ChIP-seq, RNA-seq\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double mutant rescue, multiple orthogonal readouts (epigenomic, morphological, behavioral)\",\n      \"pmids\": [\"32483278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Menin-KMT2A interaction is a critical transcriptional dependency in KMT2A-rearranged and NPM1-mutant acute leukemia; pharmacological inhibition of menin-KMT2A interaction with revumenib induces leukemic differentiation and achieves remission in patients, establishing the menin–KMT2A protein–protein interaction as the functional oncogenic dependency.\",\n      \"method\": \"First-in-human phase 1 clinical trial with mechanistic correlatives (differentiation markers, residual disease clearance); prior preclinical menin-KMT2A inhibitor studies established the interaction\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clinical proof-of-concept with mechanistic differentiation syndrome correlate; independently replicated across multiple trials (PMID 36922593, 39121437)\",\n      \"pmids\": [\"36922593\", \"39121437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Menin inhibition (loss of menin-KMT2A/B complex) paradoxically derepresses bivalent genes by redistributing KMT2A from active genes to bivalent promoters; a Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent loci.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screens, pharmacological menin inhibition, H3K4me3/H3K27me3 ChIP-seq, genetic knockout in cancer cells and pluripotent stem cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screens plus ChIP-seq with multiple genetic and pharmacological perturbations; mechanistic distinction between Menin-dependent and independent KMT2A functions\",\n      \"pmids\": [\"36635503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JNJ-75276617 (bleximenib) inhibits the menin-KMT2A protein-protein interaction; a co-crystal structure of menin with JNJ-75276617 reveals a binding mode distinct from revumenib. Inhibition displaces the menin-KMT2A complex from target gene promoters (including MEIS1 and FLT3), reducing their expression.\",\n      \"method\": \"Co-crystal structure determination, chromatin immunoprecipitation-seq, gene expression analysis, in vitro antiproliferative assays, xenograft models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus ChIP-seq plus functional validation in vitro and in vivo in a single study\",\n      \"pmids\": [\"38905635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KMT2A promotes colorectal cancer invasion and metastasis by transcriptionally activating cathepsin Z (CTSZ); p65 (NF-κB) recruits KMT2A to the CTSZ promoter, and knockdown of p65 reduces KMT2A occupancy at the CTSZ promoter.\",\n      \"method\": \"KMT2A knockdown in HCT116/DLD1 cells, in vivo xenograft metastasis model, ChIP assay showing p65 recruits KMT2A to CTSZ promoter\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP confirming promoter occupancy, KD with defined metastasis phenotype; single lab\",\n      \"pmids\": [\"31090199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A promotes melanoma cell growth by activating hTERT transcription; KMT2A knockdown reduces hTERT promoter activity and expression, and hTERT overexpression rescues the proliferation defect caused by KMT2A knockdown.\",\n      \"method\": \"KMT2A knockdown/overexpression in melanoma cell lines, hTERT promoter reporter assay, rescue experiment with hTERT overexpression, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — promoter reporter plus genetic rescue experiment plus in vivo validation; single lab\",\n      \"pmids\": [\"28726783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KMT2A promotes monocyte/macrophage expression of procoagulant (tissue factor, F3) and profibrinolytic factors (PLAU, PLAUR) and proinflammatory cytokines through NF-κB/RelA-dependent transcription; MLL1-dependent phenotypes were confirmed in a coronavirus infection model in vivo.\",\n      \"method\": \"Conditional MLL1 knockout in monocytes/macrophages using murine betacoronavirus MHVA59 model, in vitro NF-κB reporter assays, in vivo coagulation phenotype measurements, analysis of human SARS-CoV-2 positive samples\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with defined coagulation phenotype plus in vitro mechanistic NF-κB pathway placement; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"36493338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KMT2A promotes expression of METTL3 via H3K4me3 modification; METTL3-mediated m6A modification then reduces ATG4a RNA stability, impairing autophagy in nucleus pulposus cells, which drives GATA4-dependent senescence and intervertebral disc degeneration.\",\n      \"method\": \"KMT2A and METTL3 silencing in nucleus pulposus cells, ChIP for H3K4me3 at METTL3 promoter, m6A-seq/MeRIP, ATG4a RNA stability assay, autophagic flux measurement, SASP quantification\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming H3K4me3 at METTL3 promoter, m6A modification assay, RNA stability readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39572532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"An enhancer-derived lncRNA (Myrlin) physically interacts with the KMT2A/MLL1 complex and recruits it to the Myb locus; Myrlin CRISPRi reduces KMT2A occupancy at Myb, decreasing CDK9 and RNA Pol II binding and causing Pol II pausing in the Myb first exon/intron.\",\n      \"method\": \"CRISPR-Cas9 TSS deletion, CRISPRi, RNA immunoprecipitation showing Myrlin-KMT2A interaction, ChIP for KMT2A/CDK9/Pol II at Myb locus, 3C/chromosome conformation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP confirming interaction, ChIP showing loss of KMT2A occupancy upon Myrlin loss, genetic perturbations with defined transcriptional phenotype; single lab\",\n      \"pmids\": [\"38889007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of KMT2C/D in urothelium causes KMT2A-menin complex to redistribute from KMT2D-occupied enhancers to CpG-high and bivalent promoters, derepressing signal-induced immediate early genes; KMT2A-menin redistribution is a mechanistic consequence of KMT2C/D loss.\",\n      \"method\": \"Genetically engineered mouse models (Kmt2c/d knockout), ChIP-seq for KMT2A, H3K4me1, H3K27ac, nascent RNA transcription assays, functional differentiation and transformation assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with genome-wide ChIP-seq demonstrating KMT2A redistribution; multiple orthogonal epigenomic readouts\",\n      \"pmids\": [\"39806204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KMT2A missense variant p.Arg1154Trp (in the CXXC domain) causes disturbed subcellular distribution of KMT2A and alters expression of KMT2A target genes in patient fibroblasts; a variant in the transactivation domain (p.Met2853Arg) also alters target gene expression without affecting localization, demonstrating that both domains are functionally critical.\",\n      \"method\": \"Primary patient fibroblasts, immunofluorescence for subcellular localization, qRT-PCR for target gene expression\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct localization experiment with functional consequence in patient cells; single lab, limited to two variants\",\n      \"pmids\": [\"29203834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proteasome inhibition in KMT2A-rearranged infant ALL depletes histone H2B monoubiquitination (H2Bub1) and histone H3K79 dimethylation at KMT2A target genes and downregulates the KMT2A gene expression signature, indicating proteasome inhibitors target the KMT2A transcriptional complex.\",\n      \"method\": \"Drug screen in primary KMT2Ar infant ALL specimens, ChIP analysis of H2Bub1 and H3K79me2, KMT2A target gene expression profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP demonstrating loss of KMT2A-associated histone marks at target genes; single lab, primary patient specimens\",\n      \"pmids\": [\"36781850\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KMT2A (MLL1/HRX/ALL-1) is a nuclear H3K4 methyltransferase that binds DNA through AT-hook and CXXC domains, forms a menin-dependent complex that deposits activating H3K4me3 at target gene promoters (including HOXA genes, MEIS1, FLT3, hTERT, and CTSZ), maintains bivalent chromatin by opposing polycomb-mediated repression at developmental loci, recruits NF-κB/RelA for inflammatory gene transcription, and is converted to a gain-of-function oncogenic transcription factor in leukemia by chromosomal translocations that fuse its N-terminal DNA-binding region to partner proteins (ENL, AF-4/FEL, AF-9, AF-10, ELL) that contribute transcriptional activation domains, while also interacting with SET/PP2A and GADD34 complexes; disruption of the menin–KMT2A protein–protein interaction with small-molecule inhibitors (revumenib, bleximenib) displaces the complex from chromatin, downregulates target genes, and induces leukemic differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KMT2A (MLL1/HRX/ALL-1) is a nuclear histone H3K4 methyltransferase that binds DNA and deposits activating H3K4me3 to control developmental and signal-responsive gene programs [#9, #13]. It engages chromatin through its own DNA-binding modules: recombinant AT-hook subdomains bind double-stranded DNA non-sequence-specifically while a zinc-binding (CXXC) subdomain supports sequence-specific binding, and a CXXC-domain missense variant disturbs KMT2A subcellular distribution and target-gene expression in patient cells [#9, #21]. A menin-dependent KMT2A complex occupies active gene promoters; loss of the menin interaction redistributes KMT2A to bivalent promoters, revealing a menin-independent function in maintaining H3K4me3 and opposing polycomb-mediated repression, and loss of KMT2C/D similarly redirects the KMT2A-menin complex from enhancers to CpG-high and bivalent promoters [#13, #20]. KMT2A is recruited to specific targets by partner factors — NF-\\u03baB/RelA (p65) brings it to the CTSZ promoter to drive colorectal invasion and to procoagulant/proinflammatory loci in monocytes/macrophages, while an enhancer-derived lncRNA (Myrlin) recruits the KMT2A complex to the Myb locus to license productive RNA Pol II elongation [#15, #17, #19]. Through these target programs KMT2A activates transcription of genes including hTERT in melanoma and METTL3 in nucleus pulposus cells, and in hippocampal neurons it deposits locus-specific H3K4 methylation required for memory, acting in mutual antagonism with the demethylase KDM5C [#16, #18, #10, #11]. In leukemia, chromosomal translocations fuse the N-terminal AT-hook/DNA-binding region of KMT2A to partner proteins (ENL, AF-4/FEL, AF-9, AF-10, ELL) that donate transcriptional activation domains, converting it into a gain-of-function oncogenic transcription factor; the ENL C-terminal ~84\\u201390 residues are necessary and sufficient for both transactivation and transformation, and AT-hook DNA binding plus the methyltransferase-homology domain are required for the oncogenic activity [#0, #1, #3, #7]. The menin\\u2013KMT2A protein\\u2013protein interaction is the functional oncogenic dependency: small-molecule inhibitors (revumenib, bleximenib) displace the complex from target promoters such as MEIS1 and FLT3, downregulate the KMT2A signature, and induce leukemic differentiation and clinical remission [#12, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the molecular architecture of the leukemic fusions, showing that translocation partners (FEL/AF-4, ENL) are joined in-frame to the N-terminal AT-hook-containing portion of KMT2A and that the partners carry intrinsic transcriptional activation domains.\",\n      \"evidence\": \"cDNA cloning and sequencing of t(4;11) fusion transcripts; deletion mutagenesis and transcriptional reporter assays for ENL across lymphoid, myeloid, and yeast systems\",\n      \"pmids\": [\"8443374\", \"8080983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional reconstitution of the FEL fusion's transforming activity in these studies\", \"Mechanism by which the partner activation domain reprograms KMT2A targets not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified early physical partners of the KMT2A N-terminus (UNR, with cold-shock domains), beginning the mapping of its protein interaction network.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vitro binding, and co-IP from COS cells\",\n      \"pmids\": [\"8934551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the UNR interaction not established\", \"Single-lab interaction without in vivo validation\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined how KMT2A engages chromatin and assembles regulatory heterocomplexes, showing AT-hook and zinc-binding DNA-binding modes, nuclear punctate localization, and direct association with the SET\\u2013PP2A complex.\",\n      \"evidence\": \"Recombinant subdomain DNA-binding assays, immunolocalization, yeast two-hybrid, co-IP, and site-directed mutagenesis with phosphatase activity readout\",\n      \"pmids\": [\"9158002\", \"9129043\", \"9041173\", \"9353299\", \"9403001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence-specific DNA targets in vivo not identified\", \"Role of the SET\\u2013PP2A heterocomplex in normal KMT2A function unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Dissected the gain-of-function requirements of an MLL fusion, showing transformation requires KMT2A AT-hooks and methyltransferase-homology domain plus the partner's transactivation domain, directly linking transactivation to oncogenesis.\",\n      \"evidence\": \"Structure-function deletion analysis with in vitro myeloid immortalization, DNA-binding, and transactivation assays; in vivo leukemia induction by HRX-ENL\",\n      \"pmids\": [\"9418860\", \"9250666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the chromatin targets responsible for transformation\", \"Mechanistic link between DNA binding and aberrant transcription not resolved at the gene level\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected KMT2A and its fusions to apoptotic control, showing wild-type KMT2A enhances GADD34-induced apoptosis while fusions inhibit it.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, and overexpression apoptosis assays after ionizing radiation with three fusion proteins versus wild-type\",\n      \"pmids\": [\"10490642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of the GADD34 axis to leukemogenesis not demonstrated in vivo\", \"Link to KMT2A's methyltransferase activity unexplored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended KMT2A function beyond leukemia, showing locus-specific H3K4 methylation roles in neuronal memory and oncogenic activation of hTERT in melanoma.\",\n      \"evidence\": \"Mouse Kmt2a knockdown with H3K4me ChIP and memory behavior; melanoma KMT2A knockdown/overexpression with hTERT promoter reporter and rescue\",\n      \"pmids\": [\"28723559\", \"28726783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment mechanism to neuronal and hTERT loci not defined\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a recruitment logic for non-leukemic KMT2A targeting, showing NF-\\u03baB/p65 recruits KMT2A to the CTSZ promoter to drive metastasis.\",\n      \"evidence\": \"KMT2A knockdown in colorectal cells, xenograft metastasis model, and ChIP showing p65-dependent KMT2A occupancy\",\n      \"pmids\": [\"31090199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p65\\u2013KMT2A physical interaction not biochemically resolved\", \"Generality of p65-directed recruitment beyond CTSZ untested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a chromatin balance principle, showing KMT2A and the demethylase KDM5C act in mutual antagonism such that combined loss rescues single-mutant epigenomic and behavioral defects.\",\n      \"evidence\": \"Double-mutant mouse genetics with dendritic spine, behavioral, H3K4me ChIP-seq, and RNA-seq readouts\",\n      \"pmids\": [\"32483278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether antagonism is direct or via shared targets not resolved\", \"Restricted to neuronal context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the menin\\u2013KMT2A interaction as the therapeutic oncogenic dependency and distinguished menin-dependent active-gene occupancy from a menin-independent bivalent-gene function.\",\n      \"evidence\": \"First-in-human revumenib trial with differentiation correlatives; genome-wide CRISPR screens and H3K4me3/H3K27me3 ChIP-seq with genetic and pharmacological menin perturbation\",\n      \"pmids\": [\"36922593\", \"39121437\", \"36635503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of menin-independent bivalent maintenance not fully defined\", \"Determinants of redistribution between active and bivalent loci unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked KMT2A to inflammatory/coagulation transcription and to histone-mark dependencies, placing it downstream of NF-\\u03baB/RelA in macrophages and within a proteasome-sensitive H2Bub1/H3K79me2 axis in KMT2A-rearranged ALL.\",\n      \"evidence\": \"Conditional MLL1 macrophage knockout in a coronavirus model with NF-\\u03baB reporters; drug screen in primary KMT2Ar infant ALL with H2Bub1/H3K79me2 ChIP and signature profiling\",\n      \"pmids\": [\"36493338\", \"36781850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KMT2A\\u2013RelA biochemical interaction not mapped\", \"Mechanism linking proteasome activity to histone marks at KMT2A targets indirect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the structural basis and target consequences of menin\\u2013KMT2A inhibition and identified RNA-guided recruitment, showing bleximenib's distinct binding mode displaces the complex from MEIS1/FLT3 and that lncRNA Myrlin recruits KMT2A to license Myb elongation.\",\n      \"evidence\": \"Menin\\u2013inhibitor co-crystal structure with ChIP-seq and xenograft validation; RNA-IP, ChIP, and 3C at the Myb locus with CRISPRi\",\n      \"pmids\": [\"38905635\", \"38889007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of lncRNA-mediated recruitment across loci unknown\", \"How KMT2A occupancy controls Pol II pause release mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that KMT2A genomic positioning is dictated by sister methyltransferases, with KMT2C/D loss redistributing the KMT2A-menin complex from enhancers to bivalent/CpG-high promoters and derepressing immediate-early genes.\",\n      \"evidence\": \"Kmt2c/d knockout mouse models with KMT2A, H3K4me1, H3K27ac ChIP-seq and nascent transcription assays\",\n      \"pmids\": [\"39806204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether redistribution is competitive or signal-dependent not fully resolved\", \"Consequences for human tumors beyond urothelium untested here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KMT2A's catalytic H3K4 methyltransferase activity is mechanistically coupled to its diverse recruitment routes (NF-\\u03baB, lncRNAs, menin, sister KMTs) and how this determines locus-specific outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of how recruitment factors select between active and bivalent targets\", \"Direct in vivo structure of the assembled KMT2A complex on chromatin not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [13, 18, 22]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 7, 15, 16]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [10, 13, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 9, 21]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13, 20, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [15, 16, 17, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 12, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"menin-KMT2A complex\",\n      \"SET-PP2A heterocomplex\"\n    ],\n    \"partners\": [\n      \"MEN1\",\n      \"ENL\",\n      \"AFF1\",\n      \"GADD34\",\n      \"SET\",\n      \"PP2A\",\n      \"RELA\",\n      \"CSDE1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}