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A CreER-Based Random Induction Strategy for Modeling Translocation-Associated Sarcomas in Mice

¹ Department of Human Genetics and ² Howard Hughes Medical Institute, University of Utah, School of Medicine, Salt Lake City, Utah

Requests for reprints: Mario R. Capecchi, Department of Human Genetics, University of Utah, Eccles Institute of Human Genetics, 15 North 2030 East, Room 5440, Salt Lake City, UT 84112. Phone: 801-581-7096; Fax: 801-585-3425; E-mail: capecchi{at}genetics.utah.edu.

Key Words: SYT-SSX • synovial sarcoma • mouse model • conditional system • CreER

Previously, we reported modeling synovial sarcomas in mice by conditionally expressing the human t(X;18) translocation–derived SYT-SSX2 fusion protein in Myf5-expressing myoblasts. Using a tamoxifen-inducible CreER system in mice, we show here that sporadic expression of SYT-SSX2 across multiple tissue types leads to exclusive formation of synovial sarcoma–like tumors, whereas its widespread expression is lethal. Certain clinical and histologic features of tumors in this new model suggest additional nonmyoblast origin for synovial sarcoma. CreER-based sporadic expression both avoids the severe early developmental phenotypes associated with widespread SYT-SSX2 expression and better models natural pathogenesis of cancers in which transformed cells usually arise within an environment of largely normal cells. Furthermore, this strategy may recapitulate multiple potential cellular origins within a single model system. [Cancer Res 2009;69(8):3657–64]