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MAML2 (mastermind-like 2)

Identity

Other nameshMam-3
KIAA1819
HGNC (Hugo) MAML2
LocusID (NCBI) 84441
Location 11q21
Location_base_pair Starts at 95709757 and ends at 96076344 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description Spans 365 kb; 5 exons.
Transcription A major transcript of 7.5 kb.

Protein

Description 1153 aa, 125 kDa; conserved N-terminal basic domain (aa 29-92) which binds to the ankyrin repeat domain of Notch receptors; two acidic domains (aa 263-360 and 1124-1153) and a C-terminal transcriptional activation domain.
Expression Widely expressed.
Localisation Nuclear granules.
Function Mastermind-like coactivator for all four Notch receptors; forms a complex with the Notch intracellular domain (Notch ICD) and the CSL family of transcription factors (CSL: CBF1/RBP-jk, Suppressor of Hairless, LAG1), resulting in activation of the Notch target genes HES1 and HES5; functions as a CSL-dependent transcriptional coactivator for ligand-stimulated Notch.
Homology MAML1 and MAML3.

Implicated in

Entity mucoepidermoid carcinoma with t(11;19)(q21-22;p13).
Disease - Most common type of malignant salivary gland tumor;
- Second most frequent lung tumor of bronchial gland origin;
- Rare tumour in the thyroid.
The t(11;19) was found in samples from the three different sites.
Prognosis - Mucoepidermoid carcinomas have an unpredictable behaviour.
- The CRTC1-MAML2 fusion transcript was found equally in low, intermediate and high grade tumours; however, tumours lacking the fusion transcript were significantly associated with metastases; they may represent a subset of aggressive tumours.
- In another study, the median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients.
Hybrid/Mutated Gene CRTC1-MAML2; exon 1 of CRTC1 fused to exons 2-5 of MAML2. Note: CRTC1 is also known as MECT1, or WAMTP1.
Abnormal Protein CRTC1-MAML2. In the fusion protein, the first 171 aa including the basic domain of MAML2 are replaced by 42 aa of CRTC1; there are no sequence similarities in the N-terminal domains of MAML2 and CRTC1. The fusion protein activates transcription of the Notch target gene HES1 independently of both Notch ligand and CSL.
Transforming activity of CRTC1-MAML2 fusion oncoprotein is mediated by mimicking constitutive activation of cAMP signaling, by activating CREB directly.
  
Entity Warthin's tumor with t(11;19)(q21-22;p13).
Note In rare instances mucoepidermoid carcinoma may arise from or coexist with Warthin's tumors.
Disease Warthin's tumor is a salivary gland neoplasm consisting of benign epithelial and lymphoid components; malignant transformation is extremely rare.
Hybrid/Mutated Gene CRTC1-MAML2
  
Entity Clear Cell Hidradenomas of the skin with t(11;19)(q21-22;p13)
Disease Clear Cell Hidradenomas of the skin are benign sweat gland tumors of eccrine duct origin.
Hybrid/Mutated Gene CRTC1-MAML2; exon 1 of CRTC1 fused to exons 2 of MAML2.
  
Entity inv(11)(q21q23) in therapy related leukemias
Disease therapy-related acute leukemia and MDS.
Hybrid/Mutated Gene MLL-MAML2; exon 1-7 of MLL fused to exons 2-5 of MAML2.
Abnormal Protein Hybrid transcript MLL/MAML2 contains the following domains: from MLL: AT-hook, DNA-Methyltransferase; from MAML2: Q rich domain, acidic domain.
 
  

To be noted

It is amazing that a similar fusion transcript (CRTC1-MAML2) can be seen both in a benign and in a malignant tumour of the same organ: Warthin's tumor, a benign salivary gland neoplasm, and mucoepidermoid carcinoma of the salivary gland: either another event differentiate the two, or the genetic event takes place in different cell types or in a given cell type at different states of differenciation.
It has been hypothezised that CRTC1-MAML2 fusion is etiologically linked to benign and low-grade malignant tumors originating from diverse exocrine glands rather than being linked to a separate tumor entity.

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004

External links

Nomenclature
HGNC (Hugo)MAML2   16259
Cards
AtlasMAML2ID472
Entrez_Gene (NCBI)MAML2  84441  mastermind-like 2 (Drosophila)
GeneCards (Weizmann)MAML2
Ensembl (Hinxton) [Gene_View]  chr11:95709757-96076344 [Contig_View]  MAML2 [Vega]
cBioPortalMAML2
AceView (NCBI)MAML2
Genatlas (Paris)MAML2
WikiGenes84441
SOURCE (Princeton)NM_032427
Genomic and cartography
GoldenPath (UCSC)MAML2  -  11q21   chr11:95709757-96076344 -  11q   [Description]    (hg19-Feb_2009)
EnsemblMAML2 - 11q [CytoView]
Mapping of homologs : NCBIMAML2 [Mapview]
OMIM607537   
Gene and transcription
Genbank (Entrez)AB058722 AK308157 AW513171 AY040322 BC143529
RefSeq transcript (Entrez)NM_032427
RefSeq genomic (Entrez)AC_000143 NC_000011 NC_018922 NT_033899 NW_001838042 NW_004929380
Consensus coding sequences : CCDS (NCBI)MAML2
Cluster EST : UnigeneHs.745167 [ NCBI ]
CGAP (NCI)Hs.745167
Alternative Splicing : Fast-db (Paris)GSHG0006107
Gene ExpressionMAML2 [ NCBI-GEO ]     MAML2 [ SEEK ]   MAML2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8IZL2 (Uniprot)
NextProtQ8IZL2  [Medical]
With graphics : InterProQ8IZL2
Splice isoforms : SwissVarQ8IZL2 (Swissvar)
Domains : Interpro (EBI)Neuroggenic_mastermind-like_N [organisation]  
Related proteins : CluSTrQ8IZL2
Domain families : Pfam (Sanger)MamL-1 (PF09596)   
Domain families : Pfam (NCBI)pfam09596   
DMDM Disease mutations84441
Blocks (Seattle)Q8IZL2
Peptide AtlasQ8IZL2
HPRD09608
IPIIPI00064200   IPI00760841   
Protein Interaction databases
DIP (DOE-UCLA)Q8IZL2
IntAct (EBI)Q8IZL2
BioGRIDMAML2
InParanoidQ8IZL2
Interologous Interaction database Q8IZL2
IntegromeDBMAML2
STRING (EMBL)MAML2
Ontologies - Pathways
Ontology : AmiGOtranscription coactivator activity  nucleus  nucleoplasm  Golgi apparatus  transcription initiation from RNA polymerase II promoter  Notch signaling pathway  Notch signaling pathway  gene expression  nuclear speck  positive regulation of transcription from RNA polymerase II promoter  
Ontology : EGO-EBItranscription coactivator activity  nucleus  nucleoplasm  Golgi apparatus  transcription initiation from RNA polymerase II promoter  Notch signaling pathway  Notch signaling pathway  gene expression  nuclear speck  positive regulation of transcription from RNA polymerase II promoter  
Pathways : KEGGNotch signaling pathway   
Protein Interaction DatabaseMAML2
Wikipedia pathwaysMAML2
Gene fusion - rearrangments
Rearrangement : COSMICCRTC1 [19p13.11]  -  MAML2 [11q21]  
  [COSF1102] [COSF1103] 
Rearrangement : COSMICCRTC3 [15q26.1]  -  MAML2 [11q21]  
  [COSF1104] [COSF1105] 
Rearrangement : COSMICMAML2 [11q21]  -  CRTC1 [19p13.11]  
  [COSF1106] [COSF1107] 
Rearrangement : TICdbCRTC1 [19p13.11]  -  MAML2 [9p24.1]
Rearrangement : TICdbCRTC3 [15q26.1]  -  MAML2 [8q12.1]
Rearrangement : TICdbKMT2A [11q23.3]  -  MAML2 [4q35.1]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MAML2
snp3D : Map Gene to Disease84441
SNP (GeneSNP Utah)MAML2
SNP : HGBaseMAML2
Genetic variants : HAPMAPMAML2
Exome VariantMAML2
1000_GenomesMAML2 
Cancer Gene: CensusMAML2 
Somatic Mutations in Cancer : COSMICMAML2 
CONAN: Copy Number AnalysisMAML2 
Mutations and Diseases : HGMDMAML2
Mutations and Diseases : intOGenMAML2
Genomic VariantsMAML2  MAML2 [DGVbeta]
dbVarMAML2
ClinVarMAML2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM607537   
MedgenMAML2
GENETestsMAML2
Disease Genetic AssociationMAML2
Huge Navigator MAML2 [HugePedia]  MAML2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMAML2
Homology/Alignments : Family Browser (UCSC)MAML2
Phylogenetic Trees/Animal Genes : TreeFamMAML2
Chemical/Protein Interactions : CTD84441
Chemical/Pharm GKB GenePA134946327
Clinical trialMAML2
Other databases
Probes
Litterature
PubMed43 Pubmed reference(s) in Entrez
CoreMineMAML2
iHOPMAML2
OncoSearchMAML2

Bibliography

Translocation t(11;19)(q21;p13.1) as the sole chromosome abnormality in a cystadenolymphoma (Warthin's tumor) of the parotid gland.
Bullerdiek J, Haubrich J, Meyer K, Bartnitzke S
Cancer genetics and cytogenetics. 1988 ; 35 (1) : 129-132.
PMID 3180001
 
Chromosomal patterns in Warthin's tumor. A second type of human benign salivary gland neoplasm.
Mark J, Dahlenfors R, Stenman G, Nordquist A
Cancer genetics and cytogenetics. 1990 ; 46 (1) : 35-39.
PMID 2331681
 
Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.
Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, Callahan R
Genes & development. 1992 ; 6 (3) : 345-355.
PMID 1372276
 
Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma.
Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G
Cancer genetics and cytogenetics. 1994 ; 74 (2) : 77-83.
PMID 8019965
 
Conservation of the Notch signalling pathway in mammalian neurogenesis.
de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA
Development (Cambridge, England). 1997 ; 124 (6) : 1139-1148.
PMID 9102301
 
A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma.
Stenman G, Petursdottir V, Mellgren G, Mark J
Virchows Archiv : an international journal of pathology. 1998 ; 433 (6) : 579-581.
PMID 9870694
 
MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD
Nature genetics. 2000 ; 26 (4) : 484-489.
PMID 11101851
 
Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling.
Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M
The Journal of biological chemistry. 2002 ; 277 (52) : 50612-50620.
PMID 12386158
 
Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors.
Wu L, Sun T, Kobayashi K, Gao P, Griffin JD
Molecular and cellular biology. 2002 ; 22 (21) : 7688-7700.
PMID 12370315
 
t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway.
Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O'Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ
Nature genetics. 2003 ; 33 (2) : 208-213.
PMID 12539049
 
Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.
Enlund F, Behboudi A, AndrˆŠn Y, Oberg C, Lendahl U, Mark J, Stenman G
Experimental cell research. 2004 ; 292 (1) : 21-28.
PMID 14720503
 
A study of MECT1-MAML2 in mucoepidermoid carcinoma and Warthin's tumor of salivary glands.
Martins C, Cavaco B, Tonon G, Kaye FJ, Soares J, Fonseca I
The Journal of molecular diagnostics : JMD. 2004 ; 6 (3) : 205-210.
PMID 15269296
 
Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)--associated TORC1-MAML2 gene fusion.
Behboudi A, Winnes M, Gorunova L, van den Oord JJ, Mertens F, Enlund F, Stenman G
Genes, chromosomes & cancer. 2005 ; 43 (2) : 202-205.
PMID 15729701
 
Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation.
Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, Griffin JD
The EMBO journal. 2005 ; 24 (13) : 2391-2402.
PMID 15961999
 
Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene.
Behboudi A, Enlund F, Winnes M, AndrˆŠn Y, Nordkvist A, Leivo I, Flaberg E, Szekely L, Mˆ§kitie A, Grenman R, Mark J, Stenman G
Genes, chromosomes & cancer. 2006 ; 45 (5) : 470-481.
PMID 16444749
 
Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23).
Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T
Genes, chromosomes & cancer. 2007 ; 46 (9) : 813-819.
PMID 17551948
 
CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: implications for histogenesis and biologic behavior.
Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, El-Naggar AK
Genes, chromosomes & cancer. 2007 ; 46 (7) : 708-715.
PMID 17437281
 
Frequent fusion of the CRTC1 and MAML2 genes in clear cell variants of cutaneous hidradenomas.
Winnes M, Mˆlne L, Suurkˆēla M, AndrˆŠn Y, Persson F, Enlund F, Stenman G
Genes, chromosomes & cancer. 2007 ; 46 (6) : 559-563.
PMID 17334997
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2003Goran Stenman
Lundberg Laboratory for Cancer Research, Department of Pathology, Goteborg University, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden
Updated10-2007Kazumi Suzukawa, Jean Loup Huret
Department of Hematology, Institute of Clinical Medicine, University of Tsukuba (KS); Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Citation

This paper should be referenced as such :
Suzukawa, K ; Huret, JL
MAML2 (mastermind-like 2)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3):220-222.
Free online version   Free pdf version   [Bibliographic record ]
History of this paper:
Suzukawa, K ; Huret, JL. MAML2 (mastermind-like 2). Atlas Genet Cytogenet Oncol Haematol. 2008;12(3):220-222.
http://documents.irevues.inist.fr/bitstream/2042/38524/1/10-2007-MAML2ID472.pdf
URL : http://AtlasGeneticsOncology.org/Genes/MAML2ID472.html

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indexed on : Sat Oct 4 13:11:14 CEST 2014

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