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

Takeshi Fujino, Susumu Goyama, Yuki Sugiura, Daichi Inoue, Shuhei Asada, Satoshi Yamasaki, Akiko Matsumoto, Kiyoshi Yamaguchi, Yumiko Isobe, Akiho Tsuchiya, Shiori Shikata, Naru Sato, Hironobu Morinaga, Tomofusa Fukuyama, Yosuke Tanaka, Tsuyoshi Fukushima, Reina Takeda, Keita Yamamoto, Hiroaki Honda, Emi K. NishimuraYoichi Furukawa, Tatsuhiro Shibata, Omar Abdel-Wahab, Makoto Suematsu, Toshio Kitamura

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1826
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 2021 Dec

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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