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Genes Dev. 2014 Jul 15;28(14):1578-91. doi: 10.1101/gad.238733.114.

Lineage of origin in rhabdomyosarcoma informs pharmacological response.

Author information

1
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA;
2
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Germans Trias i Pujol Health Sciences Research Institute (IGTP), 08916 Badalona, Barcelona, Spain;
3
Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Joslin Diabetes Center, Cambridge, Massachusetts 02138, USA; Department of Pediatric Oncology, Dana Farber Cancer Institute, Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA;
4
Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
5
Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877, USA;
6
Department of Neurology, Department of Neurological Sciences, Glenn Laboratories for the Biology of Aging, Stanford University, Palo Alto, California 94304, USA;
7
Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Joslin Diabetes Center, Cambridge, Massachusetts 02138, USA;
8
Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA;
9
Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA;
10
Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
11
Department of Pathology, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA;
12
Department of Pathology, University of Virginia, Charlottesville, Virginia 22903, USA;
13
Department of Pathology, Oregon Health and Science University, Portland, Oregon 97239, USA;
14
Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229, USA; Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, Texas 78229, USA;
15
Department of Anatomic Pathology, Department of Molecular Genetics, Taussig Cancer Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

Abstract

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

KEYWORDS:

Pax3:Foxo1; alveolar rhabdomyosarcoma; histone; myoblast; sarcoma; satellite cell

PMID:
25030697
PMCID:
PMC4102765
DOI:
10.1101/gad.238733.114
[Indexed for MEDLINE]
Free PMC Article

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