%0 Journal Article %T Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma %A Amy J. Wagers %A Breelyn A. Wilky %A Brian P. Rubin %A Charles Keller %A David M. Loeb %A Joel E. Michalek %A Ken Kikuchi %A M. Imran Aslam %A Simone Hettmer %A Wolfram Laub %J - %D 2014 %R 10.1371/journal.pgen.1004107 %X 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 %K Yellow fluorescent protein %K Cell cycle and cell division %K Small interfering RNAs %K Cats %K Primary cell culture %K Cloning %K Mouse models %K Myoblasts %U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004107