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
KMT2A
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
4297
FUSION GENES
Show Gene Fusions

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
t(6;11)(q27;q23) /AML -->KMT2A- MLLT4 (AF6)
Disease
M5/M4 de novo and therapy related AML, T-cell ALL
Prognosis
poor
Entity name
t(9;11) (p22;q23)/AML --> KMT2A / MLLT3 (AF9)
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
t(10;11)(p12;q23) /AML --> KMT2A / MLLT10 (AF10)
Disease
M4 or M5 AML; ALL at times; therapy related AML
Prognosis
poor
Entity name
t(11;19)(q23;p13.1) /AML --> KMT2A-ELL
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:
Entity name
  • t(11;22)(q23;q11.2)/AML --> KMT2A / SEPT5 (hCDCRel)
    • Entity name
  • t(1;11)(q21;q23)/AML --> KMT2A / MLLT11 (AF1q)
    • Entity name
  • t(11;19)(q23;p13)/AML --> KMT2A / MYO1F
    • Entity name
  • t(11;22)(q23;q13) /AML --> KMT2A / EP300 (P300)
    • Entity name
  • trisomy 11/AML --> KMT2A tandem duplication
    • Entity name
  • 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

    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
    Adipose - Subcutaneous
    Adipose - Visceral
    Adrenal Gland
    Artery - Aorta
    Artery - Tibial
    Bladder
    Brain - Amygdala
    Brain - Anterior cingulate cortex
    Brain - Caudate
    Brain - Cerebellar Hemisphere
    Brain - Cerebellum
    Brain - Cortex
    Brain - Frontal Cortex
    Brain - Hippocampus
    Brain - Hypothalamus
    Brain - Nucleus accumbens
    Brain - Putamen
    Brain - Spinal cord
    Brain - Substantia nigra
    Breast - Mammary Tissue
    Cells - Cultured fibroblasts
    Cells - EBV - transformed lymphocytes
    Cervix - Ectocervix
    Cervix - Endocervix
    Colon - Sigmoid
    Colon - Transverse
    Esophagus - Gastroesophageal Junction
    Esophagus - Mucosa
    Esophagus - Muscularis
    Fallopian Tube
    Heart - Atrial Appendage
    Heart - Left Ventricle
    Kidney - Cortex
    Kidney - Medulla
    Liver
    Lung
    Minor Salivary Gland
    Muscle - Skeletal
    Nerve - Tibial
    Ovary
    Pancreas
    Pituitary
    Prostate
    Skin - Not Sun Exposed
    Skin - Sun Exposed
    Small Intestine - Terminal Ileum
    Spleen
    Stomach
    Testis
    Thyroid
    Uterus
    Vagina
    Whole Blood

    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
    cerebral cortex
    cerebellum
    hippocampus
    caudate
    thyroid gland
    parathyroid gland
    adrenal gland
    nasopharynx
    bronchus
    lung
    oral mucosa
    salivary gland
    esophagus
    stomach 1
    stomach 2
    duodenum
    small intestine
    colon
    rectum
    liver
    gallbladder
    pancreas
    kidney
    urinary bladder
    testis
    epididymis
    seminal vesicle
    prostate
    vagina
    ovary
    fallopian tube
    endometrium 1
    endometrium 2
    cervix, uterine
    placenta
    breast
    heart muscle
    smooth muscle
    skeletal muscle
    soft tissue 1
    soft tissue 2
    adipose tissue
    skin 1
    skin 2
    appendix
    spleen
    lymph node
    tonsil
    bone marrow

    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/meetings/js/web-card-_common.js

    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