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Elife. 2017 Jan 12;6. pii: e19214. doi: 10.7554/eLife.19214.

Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma.

Author information

1
Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.
2
Harvard Stem Cell Institute, Cambridge, United States.
3
GABBA Program, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
4
Molecular Medicine, Greehey Children's Cancer Research Institute, San Antonio, United States.
5
Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, United States.
6
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
7
Department of Pathology, University of Washington, Seattle, United States.
8
Department of Pathology, Massachusetts General Hospital, Boston, United States.

Abstract

Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.

KEYWORDS:

cancer biology; developmental biology; human; muscle; myf5; myoD; rhabdomyosarcoma; stem cells; zebrafish

PMID:
28080960
PMCID:
PMC5231408
DOI:
10.7554/eLife.19214
[Indexed for MEDLINE]
Free PMC Article

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