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Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

Author

Listed:
  • Shingo Komura

    (Kyoto University
    Gifu University Graduate School of Medicine)

  • Kenji Ito

    (Kyoto University
    University of Tokyo)

  • Sho Ohta

    (University of Tokyo)

  • Tomoyo Ukai

    (University of Tokyo)

  • Mio Kabata

    (Kyoto University)

  • Fumiaki Itakura

    (Kyoto University)

  • Katsunori Semi

    (Kyoto University)

  • Yutaka Matsuda

    (Kyoto University
    Chugai Pharmaceutical Co., Ltd)

  • Kyoichi Hashimoto

    (Kyoto University)

  • Hirofumi Shibata

    (Kyoto University)

  • Masamitsu Sone

    (Kyoto University)

  • Norihide Jo

    (Kyoto University)

  • Kazuya Sekiguchi

    (Kyoto University
    Kyoto University
    Kyoto University)

  • Takatoshi Ohno

    (Gifu University Graduate School of Medicine)

  • Haruhiko Akiyama

    (Gifu University Graduate School of Medicine)

  • Katsuji Shimizu

    (Gifu Municipal Hospital)

  • Knut Woltjen

    (Kyoto University
    Kyoto University)

  • Manabu Ozawa

    (University of Tokyo)

  • Junya Toguchida

    (Kyoto University
    Kyoto University
    Kyoto University)

  • Takuya Yamamoto

    (Kyoto University
    Yoshida-Konoe-cho, Sakyo-ku
    RIKEN Center for Advanced Intelligence Project (AIP)
    AMED-CREST)

  • Yasuhiro Yamada

    (Kyoto University
    University of Tokyo
    AMED-CREST)

Abstract

Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development.

Suggested Citation

  • Shingo Komura & Kenji Ito & Sho Ohta & Tomoyo Ukai & Mio Kabata & Fumiaki Itakura & Katsunori Semi & Yutaka Matsuda & Kyoichi Hashimoto & Hirofumi Shibata & Masamitsu Sone & Norihide Jo & Kazuya Sekig, 2019. "Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11745-1
    DOI: 10.1038/s41467-019-11745-1
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    Cited by:

    1. Emely Möller & Viviane Praz & Sanalkumar Rajendran & Rui Dong & Alexandra Cauderay & Yu-Hang Xing & Lukuo Lee & Carlo Fusco & Liliane C. Broye & Luisa Cironi & Sowmya Iyer & Shruthi Rengarajan & Mary , 2022. "EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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