TY - JOUR
T1 - Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
AU - Fujino, Takeshi
AU - Goyama, Susumu
AU - Sugiura, Yuki
AU - Inoue, Daichi
AU - Asada, Shuhei
AU - Yamasaki, Satoshi
AU - Matsumoto, Akiko
AU - Yamaguchi, Kiyoshi
AU - Isobe, Yumiko
AU - Tsuchiya, Akiho
AU - Shikata, Shiori
AU - Sato, Naru
AU - Morinaga, Hironobu
AU - Fukuyama, Tomofusa
AU - Tanaka, Yosuke
AU - Fukushima, Tsuyoshi
AU - Takeda, Reina
AU - Yamamoto, Keita
AU - Honda, Hiroaki
AU - Nishimura, Emi K.
AU - Furukawa, Yoichi
AU - Shibata, Tatsuhiro
AU - Abdel-Wahab, Omar
AU - Suematsu, Makoto
AU - Kitamura, Toshio
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-021-22053-y
DO - 10.1038/s41467-021-22053-y
M3 - Article
C2 - 33758188
AN - SCOPUS:85103152867
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1826
ER -