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dc.contributor.authorLee, Cheng-Han
dc.contributor.authorOu, Wen-Bin
dc.contributor.authorMarino-Enriquez, Adrian
dc.contributor.authorZhu, Meijun
dc.contributor.authorMayeda, Mark
dc.contributor.authorWang, Yuexiang
dc.contributor.authorGuo, Xiangqian
dc.contributor.authorBrunner, Alayne L.
dc.contributor.authorAmant, Frédéric
dc.contributor.authorFrench, Christopher A.
dc.contributor.authorWest, Robert B.
dc.contributor.authorMcAlpine, Jessica N.
dc.contributor.authorGilks, C. Blake
dc.contributor.authorPrentice, Leah M.
dc.contributor.authorJones, Steven J. M.
dc.contributor.authorMarra, Marco A.
dc.contributor.authorShah, Sohrab P.
dc.contributor.authorRijn, Matt van de
dc.contributor.authorHuntsman, David G.
dc.contributor.authorCin, Paola Dal
dc.contributor.authorDebiec-Rychter, Maria
dc.contributor.authorNucci, Marisa R.
dc.contributor.authorFletcher, Jonathan A.
dc.contributor.authorYaffe, Michael B
dc.contributor.authorMcPherson, Andrew
dc.date.accessioned2012-09-04T20:11:07Z
dc.date.available2012-09-04T20:11:07Z
dc.date.issued2012-01
dc.date.submitted2011-09
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/72511
dc.description.abstract14-3-3 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.isoen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1115528109en_US
dc.rightsArticle 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.sourcePNASen_US
dc.title14-3-3 fusion oncogenes in high-grade endometrial stromal sarcomaen_US
dc.typeArticleen_US
dc.identifier.citationLee, 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 Sciencesen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.approverYaffe, Michael B.
dc.contributor.mitauthorYaffe, Michael B.
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsLee, 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
dc.identifier.orcidhttps://orcid.org/0000-0002-9547-3251
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


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