Published in
Public Library of Science, PLoS Genetics, 1(10), p. e1004107, 2014
DOI: 10.1371/journal.pgen.1004107
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- Public Library of Science
- [www.ncbi.nlm.nih.gov] | PDF
- [dash.harvard.edu] | PDF
- [europepmc.org] | PDF
- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [citeseerx.ist.psu.edu] | PDF
- [www.ohsu.edu] | PDF
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Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma
,
Simone Hettmer,
M. Imran Aslam,
M. Imran Aslam,
Joel E. Michalek,
Wolfram Laub,
Breelyn A. Wilky,
David M. Loeb,
Brian P. Rubin,
Amy J. Wagers,
Charles Keller
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Abstract
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.