TY - JOUR TI - PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis AU - Kendall, Genevieve C AU - Watson, Sarah AU - Xu, Lin AU - LaVigne, Collette A AU - Murchison, Whitney AU - Rakheja, Dinesh AU - Skapek, Stephen X AU - Tirode, Franck AU - Delattre, Olivier AU - Amatruda, James F A2 - White, Richard M VL - 7 PY - 2018 DA - 2018/06/05 SP - e33800 C1 - eLife 2018;7:e33800 DO - 10.7554/eLife.33800 UR - https://doi.org/10.7554/eLife.33800 AB - Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6–19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease. KW - rhabdomyosarcoma KW - fusion oncogene KW - PAX3-FOXO1 KW - sarcoma KW - HES3 KW - muscle JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -