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- Title
PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.
- Authors
Searcy, Madeline B.; Larsen IV, Randolph K.; Stevens, Bradley T.; Zhang, Yang; Jin, Hongjian; Drummond, Catherine J.; Langdon, Casey G.; Gadek, Katherine E.; Vuong, Kyna; Reed, Kristin B.; Garcia, Matthew R.; Xu, Beisi; Kimbrough, Darden W.; Adkins, Grace E.; Djekidel, Nadhir; Porter, Shaina N.; Schreiner, Patrick A.; Pruett-Miller, Shondra M.; Abraham, Brian J.; Rehg, Jerold E.
- 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. Histologically, PAX3-FOXO1 (P3F) fusion-positive rhabdomyosarcoma (FP-RMS) resembles muscles cells, however, its cell-of-origin is less clear. Here, the authors demonstrate that P3F expression induces endothelial cells reprogramming into functional myogenic stem cells, driving the formation of FP-RMS in mouse models.
- Subjects
MYOBLASTS; RHABDOMYOSARCOMA; STEM cells; MUSCLE cells; ENDOTHELIAL cells; CELL differentiation
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43044-1