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14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma

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dc.contributor.author Lee, Cheng-Han
dc.contributor.author Ou, Wen-Bin
dc.contributor.author Mariño-Enriquez, Adrian
dc.contributor.author Zhu, Meijun
dc.contributor.author Mayeda, Mark
dc.contributor.author Wang, Yuexiang
dc.contributor.author Guo, Xiangqian
dc.contributor.author Brunner, Alayne L.
dc.contributor.author Amant, Frédéric
dc.contributor.author French, Christopher A.
dc.contributor.author West, Robert B.
dc.contributor.author McAlpine, Jessica N.
dc.contributor.author Gilks, C. Blake
dc.contributor.author Yaffe, Michael B.
dc.contributor.author Prentice, Leah M.
dc.contributor.author McPherson, Andrew
dc.contributor.author Jones, Steven J. M.
dc.contributor.author Marra, Marco A.
dc.contributor.author Shah, Sohrab P.
dc.contributor.author Rijn, Matt van de
dc.contributor.author Huntsman, David G.
dc.contributor.author Cin, Paola Dal
dc.contributor.author Debiec-Rychter, Maria
dc.contributor.author Nucci, Marisa R.
dc.contributor.author Fletcher, Jonathan A.
dc.date.accessioned 2012-09-04T20:11:07Z
dc.date.available 2012-09-04T20:11:07Z
dc.date.issued 2012-01
dc.date.submitted 2011-09
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490
dc.identifier.uri http://hdl.handle.net/1721.1/72511
dc.description.abstract 14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE–FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE–FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE–FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE–FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE–FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions. en_US
dc.language.iso en_US
dc.publisher National Academy of Sciences en_US
dc.relation.isversionof http://dx.doi.org/10.1073/pnas.1115528109 en_US
dc.rights Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. en_US
dc.source PNAS en_US
dc.title 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma en_US
dc.type Article en_US
dc.identifier.citation Lee, C.-H. et al. “14-3-3 Fusion Oncogenes in High-grade Endometrial Stromal Sarcoma.” Proceedings of the National Academy of Sciences 109.3 (2012): 929–934. Copyright ©2012 by the National Academy of Sciences en_US
dc.contributor.department David H. Koch Institute for Integrative Cancer Research at MIT en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Biology en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Biological Engineering en_US
dc.contributor.approver Yaffe, Michael B.
dc.contributor.mitauthor Yaffe, Michael B.
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dc.identifier.mitlicense PUBLISHER_POLICY en_US
dc.eprint.version Final published version en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Lee, C.-H.; Ou, W.-B.; Marino-Enriquez, A.; Zhu, M.; Mayeda, M.; Wang, Y.; Guo, X.; Brunner, A. L.; Amant, F.; French, C. A.; West, R. B.; McAlpine, J. N.; Gilks, C. B.; Yaffe, M. B.; Prentice, L. M.; McPherson, A.; Jones, S. J. M.; Marra, M. A.; Shah, S. P.; van de Rijn, M.; Huntsman, D. G.; Dal Cin, P.; Debiec-Rychter, M.; Nucci, M. R.; Fletcher, J. A. en


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