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. Nishimura, Yoichi Furukawa, Tatsuhiro Shibata, Omar Abdel-Wahab, Makoto Suematsu and Toshio Kitamura ()
Additional contact information
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
Shuhei Asada: The University of Tokyo
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

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-22053-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22053-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-22053-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().