Kikuchi, KenHettmer, SimoneAslam, M. ImranMichalek, Joel E.Laub, WolframWilky, Breelyn A.Loeb, David M.Rubin, Brian P.Wagers, AmyKeller, Charles2014-03-112014Kikuchi, Ken, Simone Hettmer, M. Imran Aslam, Joel E. Michalek, Wolfram Laub, Breelyn A. Wilky, David M. Loeb, Brian P. Rubin, Amy J. Wagers, and Charles Keller. 2014. “Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma.” PLoS Genetics 10 (1): e1004107. doi:10.1371/journal.pgen.1004107. http://dx.doi.org/10.1371/journal.pgen.1004107.1553-7390http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879462Rhabdomyosarcoma 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.en-USBiologyGeneticsCancer GeneticsGene ExpressionModel OrganismsAnimal ModelsMouseMolecular Cell BiologyCellular Stress ResponsesJournal Article2014-03-1110.1371/journal.pgen.1004107