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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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References

  1. Ellisen, L.W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).

    Article  CAS  Google Scholar 

  2. Jhappan, C. et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 6, 345–355 (1992).

    Article  CAS  Google Scholar 

  3. Wu, L., Sun, T., Kobayashi, K., Gao, P. & Griffin, J.D. Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol. Cell. Biol. 22, 7688–7700 (2002).

    Article  CAS  Google Scholar 

  4. Artavanis-Tsakonas, S., Matsuno, K. & Fortini, M.E. Notch signaling. Science 268, 225–232 (1995).

    Article  CAS  Google Scholar 

  5. Wu, L. et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat. Genet. 26, 484–489 (2000).

    Article  CAS  Google Scholar 

  6. Johansson, M. et al. Translocation 11;19 in a mucoepidermoid tumor of the lung. Cancer Genet. Cytogenet. 80, 85–86 (1995).

    Article  CAS  Google Scholar 

  7. Horsman, D.E., Berean, K. & Durham, J.S. Translocation (11;19)(q21;p13.1) in mucoepidermoid carcinoma of salivary gland. Cancer Genet. Cytogenet. 80, 165–166 (1995).

    Article  CAS  Google Scholar 

  8. El-Naggar, A.K., Lovell, M., Killary, A.M., Clayman, G.L. & Batsakis, J.G. A mucoepidermoid carcinoma of minor salivary gland with t(11;19)(q21;p13.1) as the only karyotypic abnormality. Cancer Genet. Cytogenet. 87, 29–33 (1996).

    Article  CAS  Google Scholar 

  9. Dahlenfors, R., Wedell, B., Rundrantz, H. & Mark, J. Translocation(11;19)(q14–21;p12) in a parotid mucoepidermoid carcinoma of a child. Cancer Genet. Cytogenet. 79, 188 (1995).

  10. Dahlenfors, R., Lindahl, L. & Mark, J. A fourth minor salivary gland mucoepidermoid carcinoma with 11q14–21 and 19p12 rearrangements. Hereditas 120, 287–288 (1994).

    Article  CAS  Google Scholar 

  11. Mitelman, F. Recurrent chromosome aberrations in cancer. Mutat. Res. 462, 247–253 (2000).

    Article  CAS  Google Scholar 

  12. Xu, T., Rebay, I., Fleming, R.J., Scottgale, T.N. & Artavanis-Tsakonas, S. The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev. 4, 464–475 (1990).

    Article  CAS  Google Scholar 

  13. Jarriault, S. et al. Signalling downstream of activated mammalian Notch. Nature 377, 355–358 (1995).

    Article  CAS  Google Scholar 

  14. Petcherski, A.G. & Kimble, J. Mastermind is a putative activator for Notch. Curr. Biol. 10, R471–R473 (2000).

    Article  CAS  Google Scholar 

  15. Kojika, S. & Griffin, J.D. Notch receptors and hematopoiesis. Exp. Hematol. 29, 1041–1052 (2001).

    Article  CAS  Google Scholar 

  16. Dumont, E. et al. Neoplastic transformation by Notch is independent of transcriptional activation by RBP-J signalling. Oncogene 19, 556–561 (2000).

    Article  CAS  Google Scholar 

  17. Capobianco, A.J., Zagouras, P., Blaumueller, C.M., Artavanis-Tsakonas, S. & Bishop, J.M. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. Mol. Cell. Biol. 17, 6265–6273 (1997).

    Article  CAS  Google Scholar 

  18. Petcherski, A.G. & Kimble, J. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature 405, 364–368 (2000).

    Article  CAS  Google Scholar 

  19. Wolfe, M.S. γ-Secretase inhibitors as molecular probes of presenilin function. J. Mol. Neurosci. 17, 199–204 (2001).

    Article  CAS  Google Scholar 

  20. Hsieh, J.J. et al. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein–Barr virus EBNA2. Mol. Cell. Biol. 16, 952–959 (1996).

    Article  CAS  Google Scholar 

  21. Wallberg, A.E., Pedersen, K., Lendahl, U. & Roeder, R.G. p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by Notch intracellular domains in vitro. Mol. Cell. Biol. 22, 7812–7819 (2002).

    Article  CAS  Google Scholar 

  22. Fryer, C.J., Lamar, E., Turbachova, I., Kintner, C. & Jones, K.A. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev. 16, 1397–1411 (2002).

    Article  CAS  Google Scholar 

  23. Tonon, G. et al. Spectral karyotyping combined with locus-specific FISH simultaneously defines genes and chromosomes involved in chromosomal translocations. Genes Chromosom. Cancer 27, 418–423 (2000).

    Article  CAS  Google Scholar 

  24. Greenberg, R.A. et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18, 1219–1226 (1999).

    Article  CAS  Google Scholar 

  25. Tang, H.Y. et al. Constitutive expression of the cyclin-dependent kinase inhibitor p21 is transcriptionally regulated by the tumor-suppressor protein p53. J. Biol. Chem. 273, 29156–29163 (1998).

    Article  CAS  Google Scholar 

  26. Kwon, T.K., Nagel, J.E., Buchholz, M.A. & Nordin, A.A. Characterization of the murine cyclin-dependent kinase inhibitor gene p27Kip1. Gene 180, 113–120 (1996).

    Article  CAS  Google Scholar 

  27. Beatus, P., Lundkvist, J., Oberg, C. & Lendahl, U. The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 126, 3925–3935 (1999).

    CAS  Google Scholar 

  28. Bessho, Y., Miyoshi, G., Sakata, R. & Kageyama, R. Hes7: a bHLH-type repressor gene regulated by Notch and expressed in the presomitic mesoderm. Genes Cells 6, 175–185 (2001).

    Article  CAS  Google Scholar 

  29. Winter, E., Yamamoto, F., Almoguera, C. & Perucho, M. A method to detect and characterize point mutations in transcribed genes: amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc. Natl. Acad. Sci. USA 82, 7575–7579 (1985).

    Article  CAS  Google Scholar 

  30. Ruppert, J.M., Vogelstein, B. & Kinzler, K.W. The zinc-finger protein GLI transforms primary cells in cooperation with adenovirus E1A. Mol. Cell. Biol. 11, 1724–1728 (1991).

    Article  CAS  Google Scholar 

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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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