dc.contributor.author | Lee, Cheng-Han | |
dc.contributor.author | Ou, Wen-Bin | |
dc.contributor.author | Marino-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 | Prentice, Leah M. | |
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.contributor.author | Yaffe, Michael B | |
dc.contributor.author | McPherson, Andrew | |
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 | Massachusetts Institute of Technology. Department of Biological Engineering | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | 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.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 |
dc.identifier.orcid | https://orcid.org/0000-0002-9547-3251 | |
mit.license | PUBLISHER_POLICY | en_US |
mit.metadata.status | Complete | |