IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-05085-9.html
   My bibliography  Save this article

Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis

Author

Listed:
  • Shuhei Asada

    (The University of Tokyo)

  • Susumu Goyama

    (The University of Tokyo)

  • Daichi Inoue

    (The University of Tokyo
    Memorial Sloan Kettering Cancer Center)

  • Shiori Shikata

    (The University of Tokyo)

  • Reina Takeda

    (The University of Tokyo)

  • Tsuyoshi Fukushima

    (The University of Tokyo)

  • Taishi Yonezawa

    (The University of Tokyo)

  • Takeshi Fujino

    (The University of Tokyo)

  • Yasutaka Hayashi

    (The University of Tokyo)

  • Kimihito Cojin Kawabata

    (The University of Tokyo
    Weill Cornell Medical College)

  • Tomofusa Fukuyama

    (The University of Tokyo)

  • Yosuke Tanaka

    (The University of Tokyo)

  • Akihiko Yokoyama

    (National Cancer Center Tsuruoka Metabolomics Laboratory)

  • Satoshi Yamazaki

    (The University of Tokyo)

  • Hiroko Kozuka-Hata

    (The University of Tokyo)

  • Masaaki Oyama

    (The University of Tokyo)

  • Shinya Kojima

    (The University of Tokyo)

  • Masahito Kawazu

    (The University of Tokyo)

  • Hiroyuki Mano

    (The University of Tokyo
    National Cancer Center Research Institute)

  • Toshio Kitamura

    (The University of Tokyo)

Abstract

ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.

Suggested Citation

  • Shuhei Asada & Susumu Goyama & Daichi Inoue & Shiori Shikata & Reina Takeda & Tsuyoshi Fukushima & Taishi Yonezawa & Takeshi Fujino & Yasutaka Hayashi & Kimihito Cojin Kawabata & Tomofusa Fukuyama & Y, 2018. "Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05085-9
    DOI: 10.1038/s41467-018-05085-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-05085-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-05085-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Moritz Binder & Ryan M. Carr & Terra L. Lasho & Christy M. Finke & Abhishek A. Mangaonkar & Christopher L. Pin & Kurt R. Berger & Amelia Mazzone & Sandeep Potluri & Tamas Ordog & Keith D. Robertson & , 2022. "Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05085-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.