title: t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway.
abstract: Truncation of Notch1 has been shown to cause a subtype of acute leukemia, and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice. Here we identify a new mechanism for disrupting Notch signaling in human tumorigenesis, characterized by altered function of a new ortholog of the Drosophila melanogaster Notch co-activator molecule Mastermind. We cloned the t(11;19) translocation that underlies the most common type of human malignant salivary gland tumor. This rearrangement fuses exon 1 from a novel gene of unknown function at 19p13, termed mucoepidermoid carcinoma translocated 1 (MECT1), with exons 2-5 of a novel member of the Mastermind-like gene family (MAML2) at 11q21 (ref. 3). Similar to D. melanogaster Mastermind and MAML1 (refs. 4,5), full-length MAML2 functioned as a CSL (CBF-1, suppressor of hairless and Lag-1)-dependent transcriptional co-activator for ligand-stimulated Notch. In contrast, MECT1-MAML2 activated transcription of the Notch target gene HES1 independently of both Notch ligand and CSL binding sites. MECT1-MAML2 induced foci formation in RK3E epithelial cells, confirming a biological effect for the fusion product. These data suggest a new mechanism to disrupt the function of a Notch co-activator in a common type of malignant salivary gland tumor.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute and the National Naval Medical Center, Bethesda, Maryland 20889, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Sanjay
authors.initials: S
authors.lastname: Modi
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.forename: Akihito
authors.initials: A
authors.lastname: Kubo
authors.forename: Amy B
authors.initials: AB
authors.lastname: Coxon
authors.forename: Takefumi
authors.initials: T
authors.lastname: Komiya
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Neil
authors.forename: Kristen
authors.initials: K
authors.lastname: Stover
authors.forename: Adel
authors.initials: A
authors.lastname: El-Naggar
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Ilan R
authors.initials: IR
authors.lastname: Kirsch
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Kaye
mesh_terms: D000818:Animals; D019677:Artificial Gene Fusion; D051792:Basic Helix-Loop-Helix Proteins; D018277:Carcinoma, Mucoepidermoid / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation; D015321:Gene Rearrangement; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D007621:Karyotyping; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008024:Ligands; D008156:Luciferases; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D012259:Ribonuclease, Pancreatic; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C490504:JAG2 protein, human; C430872:MAML1 protein, human; C497759:N protein, Drosophila; C085316:mam protein, Drosophila; C078493:HES1 protein, human