期刊
PLOS GENETICS
卷 10, 期 1, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1004107
关键词
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资金
- NCI [5R01CA133229]
- Burroughs-Wellcome Fund
- Harvard Stem Cell Institute
- Beckman Foundation
- Hope Street Kids
- P.A.L.S. Bermuda/St. Baldrick's
- ALSF
- Bear Necessities
- NATIONAL CANCER INSTITUTE [R01CA133229, T32CA009071, P30CA006973] Funding Source: NIH RePORTER
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.
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