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Ewing Sarcoma is a malignant bone tumor in children and young adults. Upon current multimodal therapy only ∼60% of patients are long term survivors. Due to the rarity of the disease, however, only few novel agents can be tested in clinical trials. An animal model closely recapitulating the human disease would be highly needed to more rapidly explore new therapies. Ewing sarcoma is driven by the EWS/FLI1 (EF) chimeric oncogene, an aberrant Ets transcription factor that is toxic to many cell types, but tolerated by mesenchymal stem cells (MSC). Ewing sarcoma is postulated to develop from mesenchymal progenitor cells (MPC), but transgenic approaches tolerating EF expression lack behind. EF expression was shown to induce a differentiation block in MSC but does not drive full transformation. Thus, it was hypothesized that cooperating mutations are required for sarcomagenesis. We challenged this concept in a conditional mouse model in which EWS/FLI1 is activated early during endochondral bone formation by a Prx1-driven Cre recombinase (EFPrx1). EFPrx1 mice follows Mendelian ratio, but newborns suffocated due to a malformed rib cage. Bone formation was blocked at an early chondrocytic stage. EFPrx1 mice lacked limb bones, had reduced calvaria, craniofacial abnormalities and polydactyly. We found that EF expression blocked differentiation of MSC at the pre-hypertrophic chondrocyte stage due to blocked TGF-β and enhanced Hedgehog signaling (down regulated tgfβrI/II, smad1/5, dlx5 and upregulated gli1/2 and caspase 3 mRNA expression). Moreover, EF expression blocked sox9, runx2 and osterix expression. These genes are important for bone differentian. We established MSC-like cells (MSCL) from EFPrx1 mice that self-renewed, but full transformation was absent. We ought to test if the timing of EF induction plays a role, therefor we tested many time points later that the time point described before and we found that when Prx1Cre expression and consequently EWS/FLI1 induction was delayed to a time point after birth using a tamoxifen inducible system, a significant fraction of mice developed solid tumors up to 4 months after Tamoxifen induction. The histo-pathology of the tumors resembled PAS and VIMENTIN positive small round cell tumors, and genetically an EWS/FLI1 signature was seen similar to a patient-derived Ewing sarcoma gene expression pattern. These data suggest that EWS/FLI1 can drive oncogenesis without the need for additional genetic aberrations. We propose that this transgenic mouse model could resemble a faithful model for a solid EWS/FLI1 induced tumor phenocopying human Ewing sarcoma. Citation Format: Tahereh Javaheri, Barbara Sax, Harini Nivarthi, Eleni Tomazou, Mario Mikula, Jan Pencik, Zahra Kazemi, Maximilian Kauer, Marc Wiedner, Jan Tuckermann, Michaela Schlederer, Lukas Kenner, Reinhold Erben, Malkolm Logan, Christine Hartmann, Heinrich Kovar, Richard Moriggl. A mouse model for small round cell tumors induced by the Ewing sarcoma oncogene EWS/FLI1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2014-61