KMT2A (myeloid/lymphoid or mixed lineage leukemia)

2005-10-01   Jean-Loup Huret 

Instituts für Pharmazeutische Biologie, JWG Universitaet Frankfurt\\\/Main, Biozentrum, N230, 303, Marie Curie Str. 9, D-60439 Frankfurt\\\/Main, Germany

Identity

HGNC
LOCATION
11q23.3
IMAGE
Atlas Image
LEGEND
MLL partner genes - Rolf Marschalek Nov 2002.
IMAGE
Atlas Image
LEGEND
KMT2A (myeloid/lymphoid or mixed lineage leukemia) Hybridization with Vysis LSI MLL Dual Color, Break Apart Rearrangement Probe (Abbott Molecular, US), showing the MLL (KMT2A) gene on 11q23.3 (red-green or a fused yellow signal) - Courtesy Adriana Zamecnikova.
LOCUSID
FUSION GENES

DNA/RNA

Atlas Image
MLL (11q23) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

Description

37 exons, spanning over 100 kb

Transcription

in a centromeric to telomeric direction; 13 and 15 kb; coding sequence: 11.9 kb

Proteins

Atlas Image

Description

3969 amino acids; 431 KDa; contains from N-term to C-term 3 AT hooks homologous to high mobility group proteins HMGA1 and HMGA2, binding to the minor grove of DNA; 2 speckled nuclear localisation signals; 2 repression domains RD1 and RD2: RD1 or CXXC: cystein methyl transferase, binds CpG rich DNA, has a transcriptional repression activity; RD2 recruits histone desacetylases HDAC1 and 2; 3 plant homeodomains (cystein rich zinc finger domains, with homodimerization properties), 1 bromodomain (may bind acetylated histones), and 1 plant homeodomain; these domains may be involved in protein-protein interaction; a FYRN and a FRYC domain; a transactivation domain which binds CBP ; may acetylates H3 and H4 in the HOX area; a SET domain: methyltransferase; methyltates H3, including histones in the HOX area for allowing chromatin to be open to transcription. MLL is cleaved by taspase 1 into 2 proteins before entering the nucleus: a p300/320 N-term protein called MLL-N, and a p180 C-term protein, called MLL-C. The FYRN and a FRYC domains of native MLL associate MLL-N and MLL-C in a stable complex; they form a multiprotein complex with transcription factor TFIID.
Atlas Image

Expression

wide; especially in: brain, kidney, thyroid; expressed in Taned B lymphocytes and myeloid cells

Localisation

nuclear, in punctate spots

Function

transcriptional regulatory factor; MLL may have yin-yang functions through actions of MLL-N and MLL-C (e.g. desacetylation/acetylation); MLL-N acts as a transcriptional repressor; MLL can be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation ( HOXA9 in particular).

Homology

trithorax (Drosophila), ALR (human), MLL2 (human)

Mutations

Note

MLL is implicated in at least 10 % of acute leukaemias (AL) of various types: acute lymphoblastic leukemias (ALL), acute non lymphocytic leukemias (AML), biphenotypic ALs, treatment related leukemias, infant leukemias; the prognosis is poor

Implicated in

Entity name
t(4;11)(q21;q23)/acute leukaemias --> KMT2A-AFF1 (AF4)
Disease
typically CD19+ CD10-precursor B-ALL, biphenotypic AL, at times AML (M4/M5); common in infants may be congenital; treatment related leukaemia (secondary to epipodophyllotoxins)
Prognosis
median survival < 1yr
Cytogenetics
additional chromosome anomalies are found in 1/4 of cases, one of which is the i(7q)
Hybrid gene
5 MLL-3 AF4; 12kb
Fusion protein
240 kDa protein with about 1400 aminoacids from NH2 MLL and 850 from COOH AF4 (variable breakpoints); the reciprocal may or may not be expressed
Entity name
Disease
M5/M4 de novo and therapy related AML, T-cell ALL
Prognosis
poor
Entity name
Disease
M5/M4 de novo and therapy related AML
Prognosis
the prognosis may not be as poor as in other 11q23 leukaemias in de novo cases; very poor prognosis in secondary AML cases
Cytogenetics
may be overlooked; often as a sole anomaly
Hybrid gene
variable breakpoints on both genes
Fusion protein
N-term -- AT hook and DNA methyltransferase from MLL fused to the 192 C-term amino acids from AF9 (as breakpoints are variable, this is only an example)
Entity name
Disease
M4 or M5 AML; ALL at times; therapy related AML
Prognosis
poor
Entity name
Disease
mainly M4/M5; treatment related leukemia; all ages
Prognosis
very poor
Cytogenetics
detected with R banding
Hybrid gene
5 MLL - 3 ELL
Fusion protein
AT hook and DNA methyltransferase from MLL fused to most of ELL
Oncogenesis
potential transcription factor
Entity name
t(11;19)(q23;p13.3) /acute leukaemias --> KMT2A-MLLT1 (ENL)
Disease
ALL (CD19+), biphenotypic AL, AML (M4/M5); mainly congenital; treatment-related leukaemia
Prognosis
very poor, except in rare T-cell cases
Cytogenetics
detected with G banding
Hybrid gene
5 MLL - 3 ENL
Fusion protein
AT hook and DNA methyltransferase from MLL fused to, most often, the nearly entire ENL
Entity name
Other entities:
 , 
  • t(11;22)(q23;q11.2)/AML --> KMT2A / SEPT5 (hCDCRel)
     , 
  • t(1;11)(q21;q23)/AML --> KMT2A / MLLT11 (AF1q)
     , 
  • t(11;19)(q23;p13)/AML --> KMT2A / MYO1F
     , 
  • t(11;22)(q23;q13) /AML --> KMT2A / EP300 (P300) , 
  • trisomy 11/AML --> KMT2A tandem duplication
     , 
  • t(11;17)(q23;q25)/ MDS, AML --> KMT2A / SEPT9 (MSF1, AF17q25)
  • Breakpoints

    Atlas Image

    Note

    spanning a 8 kb genomic region; between exons 5 to 11; highly variable on the partner, ranging from close to the NH2-term in MLLT1 (ENL), to near the COOH-term in MLLT3 (AF9)

    Bibliography

    Pubmed IDLast YearTitleAuthors
    75429101995Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations.Bernard OA et al
    104688491999Mll rearrangements in haematological malignancies: lessons from clinical and biological studies.Dimartino JF et al
    106375081999MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines.Huntsman DG et al
    87038351996Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias.Nilson I et al
    92473081997Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax.Prasad R et al
    86204911996Complete exon structure of the ALL1 gene.Rasio D et al
    8558942199611q23 rearrangements in acute leukemia.Rubnitz JE et al
    78373911995Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia.Schichman SA et al
    91036721997Disruption of a homolog of trithorax by 11q23 translocations: leukemogenic and transcriptional implications.Waring PM et al
    89770381996Chromosome abnormalities in leukaemia: the 11q23 paradigm.Young BD et al

    Other Information

    Locus ID:

    NCBI: 4297
    MIM: 159555
    HGNC: 7132
    Ensembl: ENSG00000118058

    Variants:

    dbSNP: 4297
    ClinVar: 4297
    TCGA: ENSG00000118058
    COSMIC: KMT2A

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000118058ENST00000389506Q03164
    ENSG00000118058ENST00000527869H7C5V8
    ENSG00000118058ENST00000529852H0YEU4
    ENSG00000118058ENST00000531904E9PR05
    ENSG00000118058ENST00000532204H0YEU4
    ENSG00000118058ENST00000533790H7C5W4
    ENSG00000118058ENST00000534358Q03164
    ENSG00000118058ENST00000647944A0A3B3ITZ6
    ENSG00000118058ENST00000649666A0A3B3ITT0
    ENSG00000118058ENST00000649690A0A3B3ISN4
    ENSG00000118058ENST00000649699Q03164
    ENSG00000118058ENST00000649878A0A3B3ITT7

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35

    Pathways

    PathwaySourceExternal ID
    Lysine degradationKEGGko00310
    Lysine degradationKEGGhsa00310
    Transcriptional misregulation in cancerKEGGko05202
    Transcriptional misregulation in cancerKEGGhsa05202
    Chromatin organizationREACTOMER-HSA-4839726
    Chromatin modifying enzymesREACTOMER-HSA-3247509
    PKMTs methylate histone lysinesREACTOMER-HSA-3214841

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    184506022008Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.422
    179571882007MLL translocations, histone modifications and leukaemia stem-cell development.410
    168781302006Regulation of MLL1 H3K4 methyltransferase activity by its core components.340
    217415972011MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.307
    151991222004Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.266
    185989422008Menin critically links MLL proteins with LEDGF on cancer-associated target genes.198
    156403492005Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.157
    160768672005Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.143
    228954302012The super elongation complex (SEC) family in transcriptional control.139
    126469572003TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23).138

    Citation

    Jean-Loup Huret

    KMT2A (myeloid/lymphoid or mixed lineage leukemia)

    Atlas Genet Cytogenet Oncol Haematol. 2005-10-01

    Online version: http://atlasgeneticsoncology.org/gene/13/kmt2a-(myeloid-lymphoid-or-mixed-lineage-leukemia)

    Historical Card

    2002-11-01 KMT2A (myeloid/lymphoid or mixed lineage leukemia) by  Rolf Marschalek 

    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

    2000-12-01 KMT2A (myeloid/lymphoid or mixed lineage leukemia) by  Jay L Hess,Jean-Loup Huret 

    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

    1997-12-01 KMT2A (myeloid/lymphoid or mixed lineage leukemia) by  Jean-Loup Huret 

    Instituts für Pharmazeutische Biologie, JWG Universitaet Frankfurt\\\/Main, Biozentrum, N230, 303, Marie Curie Str. 9, D-60439 Frankfurt\\\/Main, Germany