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 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.
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Ken
K
Kikuchi
The Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America, and Joslin Diabetes Center, Boston, Massachusetts, United States of America ; Department of Pediatric Oncology, Dana Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts, United States of America.
Simone
S
Hettmer
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
M Imran
MI
Aslam
Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas, United States of America.
Joel E
JE
Michalek
Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
Wolfram
W
Laub
Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
Breelyn A
BA
Wilky
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
David M
DM
Loeb
Departments of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.
Brian P
BP
Rubin
The Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America, and Joslin Diabetes Center, Boston, Massachusetts, United States of America.
Amy J
AJ
Wagers
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Charles
C
Keller
D000222:Adaptation, Physiological / Q000528:radiation effects; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D011827:Radiation; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D015514:Oncogene Proteins, Fusion; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors