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t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway

Nature Genetics volume 33, pages 208–213 (2003)Cite this article

An Erratum to this article was published on 01 March 2003

Abstract

Truncation of Notch1 has been shown to cause a subtype of acute leukemia1, and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice2. 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.

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Figure 1: t(11;19) rearrangement creates a MECT1–MAML2 fusion transcript.
Figure 2: MECT1–MAML2 co-localizes with ICN1, is deficient in its ability to form a ternary complex with CSL and retains a TAD.
Figure 3: MECT1–MAML2 activation is independent of Jagged2 stimulation and CSL binding sites and shows narrow promoter specificity.
Figure 4: Effect of MECT1–MAML2, MECT1–MAML1 and MECT1–VP16 on an artificial promoter containing four tandem CSL binding sites.
Figure 5: Induction of Notch target genes by the MECT1–MAML2 product in vivo.

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Acknowledgements

We are grateful to M. Kuehl, P. Aplan and T. Ried for helpful suggestions; P. Gao and J. Liu for their help; B. Baum for providing the HSY cells; M. Wolfe for providing the γ-secretase inhibitor; and A. Capobianco for advice on the RK3E assay. We acknowledge partial support by an American Society of Hematology Scholar Award and a General Motors Cancer Research Scholar Award (L.W.).

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  1. Giovanni Tonon, Sanjay Modi and Lizi Wu: These authors contributed equally to this work

Authors and Affiliations

  1. Genetics Branch, Center for Cancer Research, National Cancer Institute and the National Naval Medical Center, Bethesda, 20889, Maryland, USA

    Giovanni Tonon, Sanjay Modi, Akihito Kubo, Amy B. Coxon, Takefumi Komiya, Kristen Stover, Ilan R. Kirsch & Frederic J. Kaye

  2. Dana-Farber Cancer Institute and Department of Medicine, Adult Oncology, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Lizi Wu & James D. Griffin

  3. Pulmonary Division, Department of Medicine, National Naval Medical Center, Bethesda, Maryland, USA

    Kevin O'Neil

  4. Department of Pathology, MD Anderson Cancer Center, Houston, Texas, USA

    Adel El-Naggar

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Correspondence to Frederic J. Kaye.

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A patent application has been filed (by F.J.K. and G.T.) for the molecular diagnosis of mucoepidermoid carcinoma.

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Tonon, G., Modi, S., Wu, L. et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33, 208–213 (2003). https://doi.org/10.1038/ng1083

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