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PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

  1. Author:
    Gryder, Berkley E.
    Yohe, Marielle E.
    Chou, Hsien-Chao
    Zhang, Xiaohu
    Marques, Joana
    Wachtel, Marco
    Schaefer, Beat
    Sen, Nirmalya
    Song, Young
    Gualtieri, Alberto
    Pomella, Silvia
    Rota, Rossella
    Cleveland, Abigail
    Wen, Xinyu
    Sindiri, Sivasish
    Wei, Jun S.
    Barr, Frederic G.
    Das, Sudipto
    Andresson, Thorkell
    Guha, Rajarshi
    Lal-Nag, Madhu
    Ferrer, Marc
    Shern, Jack F.
    Zhao, Keji
    Thomas, Craig J.
    Khan, Javed

  2. Author Address

    NCI, Genet Branch, NIH, Bethesda, MD 20892 USA.NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD USA.Univ Childrens Hosp, Zurich, Switzerland.Osped Pediat Bambino Gesu Res Inst, Dept Oncohematol, Rome, Italy.NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA.NCI, Lab Prote & Analyt Technol, Adv Technol Ctr, Frederick, MD 21701 USA.NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA.
    1. Year: 2017
    2. Date: Aug
  2. Journal: Cancer Discovery
  3. AMER ASSOC CANCER RESEARCH,
    1. 7
    2. 8
    3. Pages: 884-899
  5. Type of Article: Article
  6. ISSN: 2159-8274
  1. Abstract:

    Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy.

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External Sources

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  2. DOI: 10.1158/2159-8290.CD-16-1297
  3. PMID: 28446439
  4. View record in Web of Science®
  5. WOS: 000406676000026

Library Notes

  1. Fiscal Year: FY2016-2017
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