title: Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma.
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.
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.|GABBA Program, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
authors.forename: Inês M
authors.initials: IM
authors.lastname: Tenente
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.
authors.forename: Madeline N
authors.initials: MN
authors.lastname: Hayes
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.|Molecular Medicine, Greehey Children's Cancer Research Institute, San Antonio, United States.
authors.forename: Myron S
authors.initials: MS
authors.lastname: Ignatius
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.
authors.forename: Karin
authors.initials: K
authors.lastname: McCarthy
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, United States.
authors.forename: Marielle
authors.initials: M
authors.lastname: Yohe
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, United States.
authors.forename: Sivasish
authors.identifier: 0000-0003-2516-969X
authors.initials: S
authors.lastname: Sindiri
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, United States.
authors.forename: Berkley
authors.initials: B
authors.lastname: Gryder
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.|Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Mariana L
authors.initials: ML
authors.lastname: Oliveira
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Ramakrishnan
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.
authors.forename: Qin
authors.identifier: 0000-0002-9487-570X
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Pathology, University of Washington, Seattle, United States.
authors.forename: Eleanor Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, United States.
authors.forename: G
authors.initials: G
authors.lastname: Petur Nielsen
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, United States.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Molecular Pathology, Cancer Center, and Regenerative Medicine, Massachusetts General Hospital, Boston, United States.|Harvard Stem Cell Institute, Cambridge, United States.
authors.forename: David M
authors.identifier: 0000-0001-6664-8318
authors.initials: DM
authors.lastname: Langenau
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D047369:Chromatin Immunoprecipitation; D006801:Humans; D017570:MyoD Protein / Q000378:metabolism*; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000503:physiopathology*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D015027:Zebrafish
chemical_list: C497417:MYF5 protein, human; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5
keywords: cancer biology; developmental biology; human; muscle; myf5; myoD; rhabdomyosarcoma; stem cells; zebrafish