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

Ken Kikuchi, Simone Hettmer, 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.

Original languageEnglish (US)
Article numbere1004107
JournalPLoS genetics
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Kikuchi, K., Hettmer, S., Aslam, M. I., Michalek, J. E., Laub, W., Wilky, B. A., Loeb, D. M., Rubin, B. P., Wagers, A. J., & Keller, C. (2014). Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma. PLoS genetics, 10(1), [e1004107]. https://doi.org/10.1371/journal.pgen.1004107