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Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway. 2021
Takeshi Fujino, and
Susumu Goyama, and
Yuki Sugiura, and
Daichi Inoue, and
Shuhei Asada, and
Satoshi Yamasaki, and
Akiko Matsumoto, and
Kiyoshi Yamaguchi, and
Yumiko Isobe, and
Akiho Tsuchiya, and
Shiori Shikata, and
Naru Sato, and
Hironobu Morinaga, and
Tomofusa Fukuyama, and
Yosuke Tanaka, and
Tsuyoshi Fukushima, and
Reina Takeda, and
Keita Yamamoto, and
Hiroaki Honda, and
Emi K Nishimura, and
Yoichi Furukawa, and
Tatsuhiro Shibata, and
Omar Abdel-Wahab, and
Makoto Suematsu, and
Toshio Kitamura
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
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.
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