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PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors

Author

Listed:
  • Madeline B. Searcy

    (St. Jude Children’s Research Hospital
    St. Jude Graduate School of Biomedical Sciences)

  • Randolph K. Larsen

    (St. Jude Children’s Research Hospital
    St. Jude Graduate School of Biomedical Sciences)

  • Bradley T. Stevens

    (St. Jude Children’s Research Hospital
    St. Jude Graduate School of Biomedical Sciences)

  • Yang Zhang

    (St. Jude Children’s Research Hospital)

  • Hongjian Jin

    (St. Jude Children’s Research Hospital)

  • Catherine J. Drummond

    (St. Jude Children’s Research Hospital)

  • Casey G. Langdon

    (St. Jude Children’s Research Hospital)

  • Katherine E. Gadek

    (St. Jude Children’s Research Hospital)

  • Kyna Vuong

    (St. Jude Children’s Research Hospital)

  • Kristin B. Reed

    (St. Jude Children’s Research Hospital)

  • Matthew R. Garcia

    (St. Jude Children’s Research Hospital)

  • Beisi Xu

    (St. Jude Children’s Research Hospital)

  • Darden W. Kimbrough

    (St. Jude Children’s Research Hospital
    Rhodes College)

  • Grace E. Adkins

    (St. Jude Children’s Research Hospital
    St. Jude Graduate School of Biomedical Sciences)

  • Nadhir Djekidel

    (St. Jude Children’s Research Hospital)

  • Shaina N. Porter

    (St. Jude Children’s Research Hospital)

  • Patrick A. Schreiner

    (St. Jude Children’s Research Hospital)

  • Shondra M. Pruett-Miller

    (St. Jude Children’s Research Hospital)

  • Brian J. Abraham

    (St. Jude Children’s Research Hospital)

  • Jerold E. Rehg

    (St. Jude Children’s Research Hospital)

  • Mark E. Hatley

    (St. Jude Children’s Research Hospital)

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.

Suggested Citation

  • 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. Gar, 2023. "PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43044-1
    DOI: 10.1038/s41467-023-43044-1
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    1. Gioele La Manno & Ruslan Soldatov & Amit Zeisel & Emelie Braun & Hannah Hochgerner & Viktor Petukhov & Katja Lidschreiber & Maria E. Kastriti & Peter Lönnerberg & Alessandro Furlan & Jean Fan & Lars E, 2018. "RNA velocity of single cells," Nature, Nature, vol. 560(7719), pages 494-498, August.
    2. Barbora Malecova & Sole Gatto & Usue Etxaniz & Magda Passafaro & Amy Cortez & Chiara Nicoletti & Lorenzo Giordani & Alessio Torcinaro & Marco Bardi & Silvio Bicciato & Francesca Santa & Luca Madaro & , 2018. "Dynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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    Cited by:

    1. Sara G. Danielli & Yun Wei & Michael A. Dyer & Elizabeth Stewart & Heather Sheppard & Marco Wachtel & Beat W. Schäfer & Anand G. Patel & David M. Langenau, 2024. "Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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