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
    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
    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
    380293832024Functional relevance of circRNA aberrant expression in pediatric acute leukemia with KMT2A::AFF1 fusion.1
    383172322024Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth.0
    385762842024Impact of MLL::AF9 Gene Rearrangement on Survival of Acute Myeloid Leukaemia Patients: An Insight into Pakistani Population.0
    387198572024Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts.0
    388922072024Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia.0
    389634852024The Core Complex of Yeast COMPASS and Human Mixed-Lineage Leukemia (MLL), Structure, Function, and Recognition of the Nucleosome.0
    380293832024Functional relevance of circRNA aberrant expression in pediatric acute leukemia with KMT2A::AFF1 fusion.1
    383172322024Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth.0
    385762842024Impact of MLL::AF9 Gene Rearrangement on Survival of Acute Myeloid Leukaemia Patients: An Insight into Pakistani Population.0
    387198572024Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts.0
    388922072024Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia.0
    389634852024The Core Complex of Yeast COMPASS and Human Mixed-Lineage Leukemia (MLL), Structure, Function, and Recognition of the Nucleosome.0
    349707342023Comparison of minimal residual disease measurement by multicolour flow cytometry and PCR for fusion gene transcripts in infants with acute lymphoblastic leukaemia with KMT2A gene rearrangements.1
    358337552023Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements.4
    360943602023MLL1:EZH2 Ratio in Uterine Secretions and Endometrial Receptivity in Patients with Endometriosis.0

    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/gene-explorer/gene-fusions-explorer/favicon/favicon-16x16.png

    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