Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma

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 extre...

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Bibliographic Details
Published in:PLoS genetics 2014-01, Vol.10 (1), p.e1004107
Main Authors: Kikuchi, Ken, Hettmer, Simone, Aslam, M Imran, Michalek, Joel E, Laub, Wolfram, Wilky, Breelyn A, Loeb, David M, Rubin, Brian P, Wagers, Amy J, Keller, Charles
Format: Article
Language:English
Subjects:
Adaptation, Physiological - radiation effects
Animals
Binding sites
Biology
Cancer
Cancer therapies
Cell culture
Cell cycle
Cell Cycle Checkpoints - genetics
Cell Cycle Checkpoints - radiation effects
Cell Line, Tumor
Chemotherapy
Forkhead Box Protein O1
Forkhead Transcription Factors - biosynthesis
Forkhead Transcription Factors - genetics
Gene expression
Gene Expression Regulation, Neoplastic - radiation effects
Genes
Genetic aspects
Humans
Kinases
Medical prognosis
Mice
Oncogene Proteins, Fusion - biosynthesis
Oncogene Proteins, Fusion - genetics
Paired Box Transcription Factors - biosynthesis
Paired Box Transcription Factors - genetics
PAX3 Transcription Factor
Prognosis
Protein expression
Proteins
Radiation
Rhabdomyosarcoma
Rhabdomyosarcoma - genetics
Rhabdomyosarcoma - pathology
Risk factors
Sarcoma
Studies
Translocation, Genetic
Tumors
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1004107