論文

国際誌
2021年3月23日

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

Nature communications
  • 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 Nishimura
  • Yoichi Furukawa
  • Tatsuhiro Shibata
  • Omar Abdel-Wahab
  • Makoto Suematsu
  • Toshio Kitamura
  • 全て表示

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1
開始ページ
1826
終了ページ
1826
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41467-021-22053-y

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.

リンク情報
DOI
https://doi.org/10.1038/s41467-021-22053-y
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33758188
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988019
ID情報
  • DOI : 10.1038/s41467-021-22053-y
  • PubMed ID : 33758188
  • PubMed Central 記事ID : PMC7988019

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