PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors
Madeline B Searcy, Randolph K. Larsen, Bradley T. Stevens, Yang Zhang, Hongjian Jin, Catherine J. Drummond, Casey G. Langdon, Katherine E. Gadek, Kyna Vuong, Kristin B. Reed, Matthew R. Garcia, Beisi Xu, Darden W. Kimbrough, Grace E. Adkins, Nadhir Djekidel, Shaina N. Porter, Patrick Schreiner, Shondra M. Pruett‐Miller, Brian J. Abraham, Jerold E. Rehg, Mark E. Hatley
Abstract
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.