Abstract 3284: Unfavorable outcomes of EWS-FLI1 expression in different tissues of a transgenic mouse model

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Abstract Ewing sarcoma is an aggressive neoplasm of the bone and soft tissue that arises during adolescence. It is characterized by a pathognomonic translocation between the EWS and FLI1 gene that is present in about 95% of cases. The resulting chimeric oncoprotein has been shown to be the driver of the disease where other genetic aberrations are rare. A mouse model that closely recapitulates the disease will enormously assist efforts to understand the initiation and progression of the disease. It would also facilitate drug discovery efforts. Expression of EWS-FLI1 in most cells causes cell cycle arrest and apoptosis. The tolerability of EWS-FLI1 expression, hence its ability to confer tumorigenicity may be cell type dependent. However, the cell of origin for Ewing sarcoma is still unknown which has contributed to the lack of a clinically relevant transgenic mouse model for the disease. Herein, we have employed different strategies to express EWS-FLI1 in vivo to potentially drive Ewing sarcoma development in mice. We used a conditional transgenic mouse model where EWS-FLI1 is knocked-in into Rosa26 locus (Rosa26-loxP-stop-loxP-EWS-FLI1). Expression of EWS-FLI1 in this model is rendered inactive unless cre mediated recombination occurs. In our first model, we employed adenovirus mediated cre delivery through intramuscular (IM), intraperitoneal (IP), and intravenous (IV) injection at different ages. In the IM injected mice, we observed muscle loss, limping, and clasping of hind leg in the Ad5-cre injected leg, but not in the Ad5-eGFP injected leg. This phenotype was more evident in those injected at 1 day old compared to 1 week old injected mice. In the IP injected animals, abdominal distention and shortened intestine were observed. Whereas in the IV injected mice, no evident phenotype was observed. None of the Ad5-cre injected mice developed sarcoma. In our second model, we expressed EWS-FLI1 in the osteoblast progenitors by crossing Rosa26-loxP-stop-loxP-EWS-FLI1 mice with inducible Tet-Off-based Osterix-cre mice. Expression of EWS-FLI1 in cells with activated Osterix promoter was embryonically lethal. If we delay cre expression, hence EWS-FLI1 expression, until after birth the mice develop facial bone deformity. As previously published, Osterix-cre mediated deletion of p53 and Rb (Osx-cre; p53fl/fl; pRbfl/fl) results in osteosarcoma. Interestingly, when we crossed Rosa26-loxP-stop-loxP-EWS-FLI1 mice with Osterix-cre; p53fl/fl; pRbfl/fl mice, we did not observe any sarcoma instead the mice developed leukemia. In conclusion, despite the desperate need for a mouse model for this aggressive disease, most attempts have come short. We hope our findings herein will help unravel the paradoxical biological activity of this fusion protein. We also anticipate that it will assist others to devise alternative strategies that could engender Ewing sarcomagenesis. Citation Format: Tsion Z. Minas, Jenny Han, Sung-Hyeok Hong, Tahereh Javaheri, Michaela Schlederer, Lukas Kenner, Richard Moriggl, Jeffrey Toretsky, Aykut Uren. Unfavorable outcomes of EWS-FLI1 expression in different tissues of a transgenic mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3284. doi:10.1158/1538-7445.AM2015-3284