14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma
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 thro...
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National Academy of Sciences
2012
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| Online Access: | http://hdl.handle.net/1721.1/72511 https://orcid.org/0000-0002-9547-3251 |
| _version_ | 1811095846324797440 |
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| author | Lee, Cheng-Han Ou, Wen-Bin Marino-Enriquez, Adrian Zhu, Meijun Mayeda, Mark Wang, Yuexiang Guo, Xiangqian Brunner, Alayne L. Amant, Frédéric French, Christopher A. West, Robert B. McAlpine, Jessica N. Gilks, C. Blake Prentice, Leah M. Jones, Steven J. M. Marra, Marco A. Shah, Sohrab P. Rijn, Matt van de Huntsman, David G. Cin, Paola Dal Debiec-Rychter, Maria Nucci, Marisa R. Fletcher, Jonathan A. Yaffe, Michael B McPherson, Andrew |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Lee, Cheng-Han Ou, Wen-Bin Marino-Enriquez, Adrian Zhu, Meijun Mayeda, Mark Wang, Yuexiang Guo, Xiangqian Brunner, Alayne L. Amant, Frédéric French, Christopher A. West, Robert B. McAlpine, Jessica N. Gilks, C. Blake Prentice, Leah M. Jones, Steven J. M. Marra, Marco A. Shah, Sohrab P. Rijn, Matt van de Huntsman, David G. Cin, Paola Dal Debiec-Rychter, Maria Nucci, Marisa R. Fletcher, Jonathan A. Yaffe, Michael B McPherson, Andrew |
| author_sort | Lee, Cheng-Han |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:30:48Z |
| format | Article |
| id | mit-1721.1/72511 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:30:48Z |
| publishDate | 2012 |
| publisher | National Academy of Sciences |
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| spelling | mit-1721.1/725112022-10-02T08:10:35Z 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma Lee, Cheng-Han Ou, Wen-Bin Marino-Enriquez, Adrian Zhu, Meijun Mayeda, Mark Wang, Yuexiang Guo, Xiangqian Brunner, Alayne L. Amant, Frédéric French, Christopher A. West, Robert B. McAlpine, Jessica N. Gilks, C. Blake Prentice, Leah M. Jones, Steven J. M. Marra, Marco A. Shah, Sohrab P. Rijn, Matt van de Huntsman, David G. Cin, Paola Dal Debiec-Rychter, Maria Nucci, Marisa R. Fletcher, Jonathan A. Yaffe, Michael B McPherson, Andrew Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Yaffe, Michael B. Yaffe, Michael B. 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. 2012-09-04T20:11:07Z 2012-09-04T20:11:07Z 2012-01 2011-09 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/72511 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 https://orcid.org/0000-0002-9547-3251 en_US http://dx.doi.org/10.1073/pnas.1115528109 Proceedings of the National Academy of Sciences 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. application/pdf National Academy of Sciences PNAS |
| spellingShingle | Lee, Cheng-Han Ou, Wen-Bin Marino-Enriquez, Adrian Zhu, Meijun Mayeda, Mark Wang, Yuexiang Guo, Xiangqian Brunner, Alayne L. Amant, Frédéric French, Christopher A. West, Robert B. McAlpine, Jessica N. Gilks, C. Blake Prentice, Leah M. Jones, Steven J. M. Marra, Marco A. Shah, Sohrab P. Rijn, Matt van de Huntsman, David G. Cin, Paola Dal Debiec-Rychter, Maria Nucci, Marisa R. Fletcher, Jonathan A. Yaffe, Michael B McPherson, Andrew 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma |
| title | 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma |
| title_full | 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma |
| title_fullStr | 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma |
| title_full_unstemmed | 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma |
| title_short | 14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma |
| title_sort | 14 3 3 fusion oncogenes in high grade endometrial stromal sarcoma |
| url | http://hdl.handle.net/1721.1/72511 https://orcid.org/0000-0002-9547-3251 |
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