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FLASH GENE
Symbol KMT2A contributors: shn/pgu/mct - updated : 17-11-2014
HGNC name lysine (K)-specific methyltransferase 2A
HGNC id 7132
Corresponding disease
MLLAL MLL-associated leukemia
WDSS Wiedemann-Steiner Syndrome
Location 11q23.3      Physical location : -
Synonym name
  • trithorax-like protein
  • CDK6/MLL fusion protein
  • MLL/GAS7 fusion protein
  • MLL/GMPS fusion protein
  • zinc finger protein HRX
  • MLL-AF4 der(11) fusion protein
  • mixed-lineage leukemia 1
  • lysine N-methyltransferase 2A
  • myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila)
  • Synonym symbol(s) ALL1, TRX1, HRX, CXXC7, HTRX1, MLL1A, MLL1, FLJ11783, MLL/GAS7, TET1-MLL, MLL
    EC.number 2.1.1.43
    DNA
    TYPE functioning gene
    STRUCTURE 88.73 kb     36 Exon(s)
    regulatory sequence scaffold attachement regions/matrix attachement regions
    HSs hypertensive site
    text structure several SARs in the breakpoint cluster region
    MAPPING cloned Y linked N status confirmed
    Map cen - D11S4195 - D11S1341 - MLL - D11S1364 - D11S410 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    36 - 14982 431 3969 brain, cerebral cortex, cerebellum, spinal cord, colon, liver, fetal liver, spleen, thymus, tonsil, kidney, heart, thyroid, lung, testis and lymphoid tissues 2010 20677832
    - - 16608 - 3972 - 2012 22795537
    EXPRESSION
    Type widely
    constitutive of
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Nervousbrain    
    Respiratorylung    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • three AT hooks, three nuclear and subnuclear localization signals (NLS)
  • two speckled nuclear localization signals
  • a CXXC DNA binding domain homolog to DNA methyl CpG binding domain
  • two vestigial and four PHD (C4-H-C3) zinc finger domains (PHD3 interact with the RNA-recognition motif (RRM) domain of PPIE, and can potentially act as a switch between activation and repression)
  • two conserved cleavage sites (CS1, CS2)
  • an atypical bromodomain, a FYRN domain
  • homeo domain at the C terminus, and an isolated MLL1 SET domain that is a slow monomethyltransferase , implicated in protein lysine methylation
  • a repression domain
  • C-terminal region containing the FYRC motif, the conserved WDR5 interaction (WIN) motif, and the SET domain
  • mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Mll1, Rattus norvegicus
    ortholog to Mll1, Mus musculus
    Homologene
    FAMILY
  • SET1 family of H3K4 methyltransferases
  • TRX/MLL subfamily
  • TRXG member
  • CATEGORY transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus
    basic FUNCTION
  • involved in chromatin remodeling
  • targets SET domain methyltransferase activity to Hox gene promoters
  • implicated in regulating the maintenance of Hox gene expression and hematopoiesis
  • assembles a supercomplex of proteins involved in transcriptional regulation
  • promoting cell cycle arrest and monocytic differentiation
  • invoved in CDKN1B expression and in reguating the balance between quiescence and proliferation in hematopoietic stem cells
  • a crucial role for MLL in the maintenance of memory Th2 cell function
  • a critical role for Mll in regulating stem cell self-renewal
  • catalyzes histone H3 lysine 4 methylation and is regulated by interaction with WDR5, RBBP5 (retinoblastoma-binding protein-5), and ASH2L
  • normally associated with transcriptionally active chromatins (G1 phase), dissociates from condensed mitotic chromatin and returns at the end of telophase when the nucleus starts to relax
  • might exert a function at telomeres, possibly by regulating telomere transcription and the establishment or maintenance of telomeric chromatin
  • may be required both for telomere capping and for the response to telomere uncapping
  • required for neurogenesis in the postnatal brain
  • plays a critical role in epigenetic regulation of gene expression and is a frequent target of chromosomal translocations leading to leukemia
  • regulates expression of a large number of genes during embryonic development and hematopoiesis
  • required for transcription of genes involved in hematopoiesis and development
  • histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4
  • is a key factor in hypoxia signaling, vasculogenesis and tumor growth, and its depletion suppresses tumor growth
  • epigenetic transcriptional regulator that controls proliferative expansion of immature hematopoietic progenitors, whose aberrant activation triggers leukemogenesis
  • becomes functional through intra-molecular interaction not by proteolytic processing
  • important epigenetic regulator during development and has an especially well-defined role in hematopoiesis
  • CELLULAR PROCESS cell life, proliferation/growth
    nucleotide, chromatin organization, remodeling
    nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    text control of cell proliferation
    PATHWAY
    metabolism
    signaling
    DDB1-CUL4A and MLL1 complexes constitute a novel pathway that mediates CDKN2A activation during oncogenic checkpoint response and is repressed by the polycomb repression complexes during normal growth of young cells
    a component
  • part of COMPASS-like complex
  • MEN1 acts as a scaffold protein to assemble a MEN1–MLL–PSIP1 ternary complex to coordinate gene transcription and promote MLL-fusion-protein-induced leukaemogenesis
  • super elongation complex (SEC) consists of the POLR2A elongation factors ELL, CCNT1 and several frequent KMT2A translocation partners (PMID;
  • INTERACTION
    DNA DNA binding
    RNA
    small molecule
    protein
  • member of a multiprotein supercomplex composed of > or =29 proteins including TFIID (including TBP), SWI/SNF, NuRD, hSNF2H, and Sin3A
  • C20orf13
  • MYST1 zinc finger domain
  • AFF1 in MLL/AFF1 fusion gene (regulating CDKN1B)
  • WDR5 (WDR5 recognizes Arg-3765 of MLL, which is essential for the assembly and enzymatic activity of the MLL core complex)
  • CXXC1 (interacts with MLL1, MLL2 as well as SETD1A and plays critical roles in regulations of MLL target genes)
  • member of MYST family histone acetyl transferases, homolog of Drosophila MOF
  • Histone deacetylase 1 (HDAC1)
  • Polycomb group proteins HPC2 and BMI1 polycomb ring finger oncogene (BMI-1) and the corepressor C-terminal-binding protein (CTBP1)
  • CREB-binding protein (CREBBP)
  • interacting with PPIE, which negatively regulates the function of MLL
  • growth arrest and DNA-damage-inducible 34 (GADD34)
  • SET nuclear oncogene (SET)
  • menin (MEN1)
  • preferentially binds H3K4me3
  • role of the interaction between KAT6A and KMT2A in CD34+ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which KAT6A or KMT2A deregulation leads to leukemogenesis
  • ESR1, ESR2 coordinate with MLL and MLL3 in E2-mediated transcriptional regulation of HOXB9
  • multiple lineage leukemia gene (KMT2A) and DOT1L associations with the IgH gene were also impaired in the absence of ELL2
  • MEN1 interacts with MLL, a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription
  • WDR5 binds the conserved WDR5 interaction (Win) motif of KMT2A, an interaction that is required for the H3K4 dimethylation activity of the KMT2A core complex
  • FRAT2 mediates the oncogenic activation of RAC1 by KMT2A fusions
  • RNF20 is a key requirement for KMT2A-fusion leukemia through regulatory cross talk with DOT1L
  • FLT3-mediated inhibition of hematopoiesis in KMT2A-AFF1-expressing hESCs, which is associated with large transcriptional changes and downregulation of genes involved in hematopoietic system development and function
  • SYMPK interacts and co-localizes with both KAT6A and KDMT2A in immature hematopoietic cells
  • KMT2A collaborate with ESR1 to regulate HOXA10 expression in AML
  • ASH1L cooperated functionally with KMT2A, as combined loss of ASH1L and KMT2A, but not isolated ASHLl or KMT2A deficiency, induced overt hematopoietic failure
  • PSIP1 interactions with transcriptional repressor CDCA7L and domesticated transposase POGZ, and the POGZ interaction is nearly identical to the interaction of PSIP1 with KMT2A
  • cell & other
    REGULATION
    Other cleaved by taspase threonine aspartase 1 generating N320 and C180 fragments, which heterodimerize to stabilize the complex and confer its subnuclear destination
    ASSOCIATED DISORDERS
    corresponding disease(s) MLLAL , WDSS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    in infant acute lymphoblastic T cell leukemia with translocations with 1(p32), 1(q21), 2(q11), 4(q21), 5(q31), 6(q27), 9(p22), 10(p12), 10(q22), 17(q21), 19(p13), X(q13)
    tumoral fusion      
    with AF1Q, F10, AF4L, EEN, ELL, EPS15, LAF4, MLLT2, MLLT4, MLLT3, MLLT6, FOXO4, MLLT1, FBP17, SEPT6, SEPT9, CXXC6 in infant acute lymphoblastic or myeloid T cell leukemia
    tumoral   deletion    
    intragenic duplication, also in acute myeloid leukemia with partial deletion, maybe also involving dominant negative forms of the antileukemic transcription factor Ikaros (ZNFN1A1)
    tumoral fusion      
    fused to LPP in translocation t(3;11)(q28;q23) in a secundary acute leukemia
    tumoral   translocation    
    involves MLL, MLLT3, and CCDC94 in the pathogenesis of acute myeloid leukemia with t(9;11;19)(p22;q23;p13.3)
    tumoral   translocation    
    in lymphoid leukemia, with t(4;11)(p12;q23) resulting in the creation of a chimeric RNA encoding a putative fusion protein containing 1,362 amino acids from the NH2-terminal part of MLL and 712 amino acids from the COOH-terminal part of FRYL
    constitutional     --low  
    results in cell cycle arrest at the G2/M phase
    tumoral fusion      
    MLL-KIAA0284 fusion gene in a patient with secondary acute myeloid leukemia and t(11;14)(q23;q32)(
    tumoral fusion      
    with NEBL in a case of acute myeloid leukemia in an infant
    tumoral   translocation    
    in diffuse large B-cell lymphomas
    tumoral fusion      
    SEPTIN11/KMT2A in acute lymphoblastic leukemia (ALL)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    disruption of interaction between DOT1L and MLLT3/MLLT1 is a promising therapeutic strategy with potentially fewer adverse effects than enzymatic inhibition of DOT1L for KMT2A fusion protein-associated leukemia
    cancer  
    potential role in novel cancer therapy.
    ANIMAL & CELL MODELS
  • Mll heterozygous (+/-) mice have retarded growth, haematopoietic abnormalities, and demonstrate bidirectional homeotic transformations of the axial skeleton and sternal malformations. Mll deficiency (-/-) mouse is embryonic lethal
  • primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene transplantated into immunodeficient mice generate myeloid or lymphoid acute leukemias
  • Mice with Mll expression conditionally deleted in the hematopoietic system have grossly normal hematopoiesis in bone marrow, thymus, and spleen