Affinage

KMT2A

Histone-lysine N-methyltransferase 2A · UniProt Q03164

Round 2 corrected
Length
3969 aa
Mass
431.8 kDa
Annotated
2026-04-28
130 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    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

    PMID:1720549

    Open questions at the time
    • No protein product or enzymatic activity characterized
    • Normal cellular function unknown
  2. 1992 High

    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

    PMID:1423624 PMID:1423625

    Open questions at the time
    • No enzymatic activity demonstrated
    • Mechanism of fusion-mediated transformation unknown
  3. 1995 High

    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

    PMID:7658717 PMID:7662954 PMID:8134107 PMID:8389614

    Open questions at the time
    • What the N-terminal domains contribute molecularly beyond DNA binding
    • Why structurally diverse partners all produce leukemia
  4. 1997 High

    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

    PMID:9129043 PMID:9250666 PMID:9403001

    Open questions at the time
    • Enzymatic activity of wild-type KMT2A protein still unknown
    • Mechanism by which ENL contributes transformation activity unresolved
  5. 1999 High

    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

    PMID:10490642

    Open questions at the time
    • Whether GADD34 interaction is required for leukemogenesis in vivo
    • How wild-type KMT2A promotes apoptosis molecularly
  6. 2002 High

    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

    PMID:12453419

    Open questions at the time
    • Minimal complex required for catalytic activity not defined
    • Whether SET domain loss in fusion proteins is sufficient for transformation
  7. 2004 High

    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

    PMID:15199122

    Open questions at the time
    • Whether menin is also required for oncogenic KMT2A fusions (answered the next year)
  8. 2005 High

    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

    PMID:15960974 PMID:15960975 PMID:16239140

    Open questions at the time
    • Structural basis of menin–KMT2A interaction at atomic resolution
    • Whether menin inhibition is therapeutically feasible
  9. 2006 High

    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

    PMID:16878130

    Open questions at the time
    • Full-length complex structure not determined
    • Regulation of processivity (mono- vs. di- vs. trimethylation) unclear
  10. 2011 High

    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

    PMID:21741597

    Open questions at the time
    • Whether all KMT2A fusion partners converge on DOT1L recruitment
    • Therapeutic window for DOT1L inhibition in patients
  11. 2017 Medium

    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

    PMID:29203834

    Open questions at the time
    • Genotype–phenotype correlations across the full WSS mutation spectrum incomplete
    • Tissue-specific consequences of individual domain mutations not explored in vivo
  12. 2020 Medium

    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

    PMID:32483278

    Open questions at the time
    • Which specific neuronal target genes require the KMT2A–KDM5C balance
    • Whether this mechanism operates in human neurodevelopmental disease
  13. 2023 High

    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

    PMID:36635503

    Open questions at the time
    • Long-term consequences of bivalent gene derepression during menin inhibitor therapy
    • Whether KMT2A redistribution varies across tissue types
  14. 2025 High

    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

    PMID:39806204

    Open questions at the time
    • Whether paralog redistribution occurs in other epithelial cancers with KMT2C/D loss
    • Structural basis for preferential KMT2A targeting to CpG-rich promoters

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0016740 transferase activity 4 GO:0042393 histone binding 3 GO:0003677 DNA binding 2
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3
Partners
ASH2LCSDE1DOT1LHCFC1KAT8MEN1RBBP5WDR5
Complex memberships
MLL1-MOF complexMLL1/COMPASS-like complex (MLL1-SET/WDR5/RbBP5/Ash2L)Menin-KMT2A complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 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. Molecular cloning, Southern/Northern blotting, sequence analysis, cell line characterization Cell High 1423624
1992 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. Molecular cloning, Southern blotting, Northern blotting, sequence analysis Cell High 1423625
1991 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. YAC clone mapping, molecular cloning, transcription unit identification Proceedings of the National Academy of Sciences of the United States of America High 1720549
1993 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. Southern blot analysis across 35 leukemia cases Blood High 8389614
1993 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. cDNA cloning, sequence analysis, Northern blotting Blood High 8443374
1997 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. Immunocytochemistry with polyclonal/monoclonal antibodies, Western blotting of cell lines with t(11;19) and t(4;11) translocations Blood High 9129043
1997 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. Retroviral gene transfer, in vitro colony replating assays, suspension culture immortalization, syngeneic/SCID mouse leukemia transplantation The EMBO journal High 9250666
1997 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. Immunofluorescence microscopy in transfected cells and leukemia blasts Cancer research Medium 9041173
1999 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. Yeast two-hybrid screening, co-immunoprecipitation, apoptosis assays (transfection, ionizing radiation treatment) Molecular and cellular biology High 10490642
1995 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. Southern analysis, RT-PCR, sequence analysis of leukemia specimens Blood High 7662954
1994 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. Molecular cloning, cDNA characterization, sequence analysis Oncogene Medium 8134107
1996 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. Yeast two-hybrid screening, in vitro binding studies, co-immunoprecipitation in COS cells Oncogene Medium 8934551
2002 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. Biochemical purification, mass spectrometry identification of complex members, histone methyltransferase assays, chromatin immunoprecipitation Molecular cell High 12453419
2004 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. Biochemical purification, co-immunoprecipitation, RNAi knockdown, gene expression analysis Molecular and cellular biology High 15199122
2005 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. Immunoaffinity purification, reciprocal co-immunoprecipitation, cosedimentation, in vitro chromatin transcription assay, ChIP Cell High 15960975
2005 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. Co-immunoprecipitation, nucleosome binding assays, RNAi knockdown in human cells, Xenopus morpholino knockdown Cell High 15960974
2005 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. Co-immunoprecipitation, retroviral transformation assays, conditional genetic ablation, gene expression analysis, ChIP Cell High 16239140
2006 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. Biochemical reconstitution, in vitro histone methyltransferase assay, crystal structure analysis of WDR5, in vivo transcriptional assays Nature structural & molecular biology High 16878130
2007 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. Review synthesizing biochemical, genetic, and cell biological evidence from multiple studies Nature reviews. Cancer High 17957188
2011 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. ChIP-seq (H3K79me2, H3K4me3, H3K27me3, H3K36me3), genetic Dot1l inactivation, gene expression profiling, in vivo leukemia model Cancer cell High 21741597
1997 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. Transient transcriptional reporter assays with Gal4-fusion constructs in multiple cell lines Leukemia research Medium 9403001
2014 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. Morpholino antisense knockdown, dominant-negative expression, zebrafish embryo phenotyping Developmental neurobiology Medium 25284327
2017 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. shRNA knockdown, methylation analysis, constitutively active NOTCH constructs, cell proliferation assays, zebrafish in vivo transplantation Oncotarget Medium 28968975
2017 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. shRNA knockdown, promoter-reporter assays, rescue overexpression, tumorsphere assay, xenograft mouse model Cell death & disease Medium 28726783
2020 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. Mouse genetic models (single and double knockouts), dendritic spine morphology, behavioral assays (aggression), transcriptomic profiling, H3K4 methylation analysis Communications biology Medium 32483278
2017 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. Splice assay in patient cells, Western blotting, qRT-PCR of target genes in patient fibroblasts, subcellular localization studies European journal of human genetics : EJHG Medium 29203834
2019 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. Inducible transgenic mouse model, repopulation assays, cell cycle analysis, gene expression profiling, pharmacological inhibitor testing Haematologica Medium 31558671
2023 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. Whole-genome CRISPR-Cas9 screens, pharmacological Menin inhibition, ChIP-seq, gene expression profiling in cancer cells and PSCs Nature cell biology High 36635503
2023 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. High-throughput drug screen in primary specimens, H2Bub1 and H3K79me2 ChIP, gene expression analysis, clinical response data Nature communications Medium 36781850
2023 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. Murine betacoronavirus infection model, conditional MLL1 ablation, ChIP, gene expression analysis, human SARS-CoV-2 patient samples Blood Medium 36493338
2024 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. ChIP for H3K4me3, m6A-seq, RNA stability assays, siRNA knockdown, IVDD patient samples and mouse models Bone research Medium 39572532
2025 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. Genetically engineered mouse models (Kmt2c/d knockout), ChIP-seq for KMT2A/menin and histone marks, nascent RNA transcription assays, EGFR inhibitor testing Nature genetics High 39806204
1995 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. Southern blot, RT-PCR, genomic sequencing of breakpoint regions in leukemia patients Leukemia Medium 7658717
2020 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. shRNA knockdown, overexpression rescue, cell viability/migration/apoptosis assays, xenograft mouse model Aging Low 32436862
2021 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. CRISPR-Cas9 engineering of KMT2A G3131S K562 cells, colony formation, flow cytometry, RT-PCR, Western blotting, whole-exome sequencing Annals of hematology Low 34228147

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The sequence of the human genome. Science (New York, N.Y.) 8428 11181995
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2013 Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet (London, England) 2223 23453885
2012 The mutational landscape of lethal castration-resistant prostate cancer. Nature 2108 22722839
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. The New England journal of medicine 1315 18450602
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2007 MLL translocations, histone modifications and leukaemia stem-cell development. Nature reviews. Cancer 965 17957188
1992 Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 924 1423624
1992 The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 854 1423625
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer cell 735 21741597
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2005 WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 668 15960974
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nature structural & molecular biology 623 16878130
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2002 ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Molecular cell 576 12453419
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