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Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

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Listed:
  • Takeshi Fujino

    (The University of Tokyo)

  • Susumu Goyama

    (The University of Tokyo)

  • Yuki Sugiura

    (Suematsu Gas Biology Project)

  • Daichi Inoue

    (Memorial Sloan−Kettering Cancer Center and Weill Cornell Medical College
    Foundation for Biomedical Research and Innovation at Kobe)

  • Shuhei Asada

    (The University of Tokyo
    Tokyo Women’s Medical University)

  • Satoshi Yamasaki

    (The University of Tokyo)

  • Akiko Matsumoto

    (The University of Tokyo)

  • Kiyoshi Yamaguchi

    (The University of Tokyo)

  • Yumiko Isobe

    (The University of Tokyo)

  • Akiho Tsuchiya

    (The University of Tokyo)

  • Shiori Shikata

    (The University of Tokyo)

  • Naru Sato

    (The University of Tokyo)

  • Hironobu Morinaga

    (Tokyo Medical and Dental University)

  • Tomofusa Fukuyama

    (The University of Tokyo)

  • Yosuke Tanaka

    (The University of Tokyo)

  • Tsuyoshi Fukushima

    (The University of Tokyo)

  • Reina Takeda

    (The University of Tokyo)

  • Keita Yamamoto

    (The University of Tokyo)

  • Hiroaki Honda

    (Tokyo Women’s Medical University)

  • Emi K. Nishimura

    (Tokyo Medical and Dental University)

  • Yoichi Furukawa

    (The University of Tokyo)

  • Tatsuhiro Shibata

    (The University of Tokyo)

  • Omar Abdel-Wahab

    (Memorial Sloan−Kettering Cancer Center and Weill Cornell Medical College)

  • Makoto Suematsu

    (Suematsu Gas Biology Project)

  • Toshio Kitamura

    (The University of Tokyo)

Abstract

Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.

Suggested Citation

  • Takeshi Fujino & Susumu Goyama & Yuki Sugiura & Daichi Inoue & Shuhei Asada & Satoshi Yamasaki & Akiko Matsumoto & Kiyoshi Yamaguchi & Yumiko Isobe & Akiho Tsuchiya & Shiori Shikata & Naru Sato & Hiro, 2021. "Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22053-y
    DOI: 10.1038/s41467-021-22053-y
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    Cited by:

    1. Muran Xiao & Shinji Kondo & Masaki Nomura & Shinichiro Kato & Koutarou Nishimura & Weijia Zang & Yifan Zhang & Tomohiro Akashi & Aaron Viny & Tsukasa Shigehiro & Tomokatsu Ikawa & Hiromi Yamazaki & Mi, 2023. "BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Hongna Zuo & Aiwei Wu & Mingwei Wang & Liquan Hong & Hu Wang, 2024. "tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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