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

doi:10.1371/journal.pgen.1004107

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

Journal article

Open access

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 and Charles Keller

PLoS genetics, Vol.10(1), pp.e1004107-e1004107

2014-01

DOI: https://doi.org/10.1371/journal.pgen.1004107

PMID: 24453992

Appears in UM Open Access Research Published in PloS

Abstract

Adaptation, Physiological - radiation effects

Animals

Cell Cycle Checkpoints - genetics

Cell Cycle Checkpoints - radiation effects

Cell Line, Tumor

Forkhead Box Protein O1

Forkhead Transcription Factors - biosynthesis

Forkhead Transcription Factors - genetics

Gene Expression Regulation, Neoplastic - radiation effects

Humans

Mice

Oncogene Proteins, Fusion - biosynthesis

Oncogene Proteins, Fusion - genetics

Paired Box Transcription Factors - biosynthesis

Paired Box Transcription Factors - genetics

PAX3 Transcription Factor

Radiation

Rhabdomyosarcoma - genetics

Rhabdomyosarcoma - pathology

Translocation, Genetic

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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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.118 Soft Tissue, Bone & Nerve Cancers; 1.118.300 Rhabdomyosarcoma
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Details

Title: Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma
Creators: Ken Kikuchi - Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America
Simone Hettmer - 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
M Imran Aslam - Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America
Joel E Michalek - Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas, United States of America
Wolfram Laub - Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon, United States of America
Breelyn A Wilky - Division of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
David M Loeb - Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America
Brian P Rubin - Departments of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
Amy J Wagers - 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
Charles Keller - Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America
Publication Details: PLoS genetics, Vol.10(1), pp.e1004107-e1004107
Grant note: 5R01CA133229 / NCI NIH HHS P30 CA006973 / NCI NIH HHS Wellcome Trust T32 CA009071 / NCI NIH HHS Howard Hughes Medical Institute R01 CA133229 / NCI NIH HHS
Language: English
Resource Type: Journal article
PMID: 24453992
Record Identifier: 991031614898902976