Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma

Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.
Author Summary Rare childhood cancers can be paradigms from which important new principles can be discerned. The childhood muscle cancer rhabdomyosarcoma is no exception, having been the focus of the original 1969 description by Drs. Li and Fraumeni of a syndrome now know to be commonly caused by underlying p53 tumor suppressor loss-of-function. In our studies using a conditional genetic mouse model of alveolar rhabdomyosarcoma in conjunction with human tumor cell lines, we have uncovered that the expression level of a translocation-mediated fusion gene, Pax3:Foxo1a, is dynamic and varies during the cell cycle. Our studies support that Pax3:Foxo1a facilitate the yeast-related process of checkpoint adaptation under stresses such as irradiation. The broader implication of our studies is that distal cis elements (promoter-influencing regions of DNA) may be critical to fully understanding the function of cancer-associated translocations.