KMT2A (myeloid/lymphoid or mixed lineage leukemia)
2005-10-01 Jean-Loup Huret AffiliationInstituts 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
LEGEND
MLL partner genes - Rolf Marschalek Nov 2002.
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
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
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.
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
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
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
Entity name
Entity name
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Breakpoints
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)
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 7542910 | 1995 | Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations. | Bernard OA et al |
| 10468849 | 1999 | Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. | Dimartino JF et al |
| 10637508 | 1999 | MLL2, 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 |
| 8703835 | 1996 | Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias. | Nilson I et al |
| 9247308 | 1997 | Structure 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 |
| 8620491 | 1996 | Complete exon structure of the ALL1 gene. | Rasio D et al |
| 8558942 | 1996 | 11q23 rearrangements in acute leukemia. | Rubnitz JE et al |
| 7837391 | 1995 | Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia. | Schichman SA et al |
| 9103672 | 1997 | Disruption of a homolog of trithorax by 11q23 translocations: leukemogenic and transcriptional implications. | Waring PM et al |
| 8977038 | 1996 | Chromosome 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
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38029383 | 2024 | Functional relevance of circRNA aberrant expression in pediatric acute leukemia with KMT2A::AFF1 fusion. | 1 |
| 38317232 | 2024 | Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth. | 0 |
| 38576284 | 2024 | Impact of MLL::AF9 Gene Rearrangement on Survival of Acute Myeloid Leukaemia Patients: An Insight into Pakistani Population. | 0 |
| 38719857 | 2024 | Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts. | 0 |
| 38892207 | 2024 | Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. | 0 |
| 38963485 | 2024 | The Core Complex of Yeast COMPASS and Human Mixed-Lineage Leukemia (MLL), Structure, Function, and Recognition of the Nucleosome. | 0 |
| 38029383 | 2024 | Functional relevance of circRNA aberrant expression in pediatric acute leukemia with KMT2A::AFF1 fusion. | 1 |
| 38317232 | 2024 | Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth. | 0 |
| 38576284 | 2024 | Impact of MLL::AF9 Gene Rearrangement on Survival of Acute Myeloid Leukaemia Patients: An Insight into Pakistani Population. | 0 |
| 38719857 | 2024 | Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts. | 0 |
| 38892207 | 2024 | Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. | 0 |
| 38963485 | 2024 | The Core Complex of Yeast COMPASS and Human Mixed-Lineage Leukemia (MLL), Structure, Function, and Recognition of the Nucleosome. | 0 |
| 34970734 | 2023 | Comparison 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 |
| 35833755 | 2023 | Mutational landscape and clinical outcome of pediatric acute myeloid leukemia with 11q23/KMT2A rearrangements. | 4 |
| 36094360 | 2023 | MLL1: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
Historical Card
2002-11-01 KMT2A (myeloid/lymphoid or mixed lineage leukemia) by Rolf Marschalek Affiliation
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 Affiliation
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 Affiliation
Instituts für Pharmazeutische Biologie, JWG Universitaet Frankfurt\\\/Main, Biozentrum, N230, 303, Marie Curie Str. 9, D-60439 Frankfurt\\\/Main, Germany
