Abstract 2013: The PAX3-FOXO1 oncogene drives aneuploidy and overrides aneuploidy-associated proliferative defects in alveolar rhabdomyosarcoma

Alveolar Rhabdomyosarcoma (ARMS) is primarily defined by the t(2;13)(q35;q14) translocation, which generates the PAX3-FOXO1 oncogene. Despite the fact that ARMS are frequently aneuploid, like a majority of other solid tumors, it is unknown whether PAX3-FOXO1 contributes to the development and/or persistence of aneuploidy. In this study we show that PAX3-FOXO1 serves as the driver mutation to promote aneuploidy by globally altering gene regulatory networks essential for maintaining proper chromosome number and structure. Further, we demonstrate that PAX3-FOXO1 overrides aneuploid-dependent growth arrest by altering the expression of growth factor related regulatory networks. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these gene regulatory network changes. This is the one of the first studies describing how an oncogene and post-translational modifications of the corresponding oncoprotein drive the acquisition of aneuploidy and override proliferation defects in malignant transformation. The mechanism for PAX3-FOXO1 described in this work has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens. Citation Format: Andrew D. Hollenbach, Jacob M. Loupe, Patrick J. Miller, Benjamin P. Bonner, Elaine C. Maggi, Jyothi Vijayaraghavan, Jovanny Zabaleta, Christopher M. Taylor, Fern Miller, Judy S. Crabtree. The PAX3-FOXO1 oncogene drives aneuploidy and overrides aneuploidy-associated proliferative defects in alveolar rhabdomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2013.