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

Authors: Fujino, T.; Goyama, S.; Sugiura, Y.; Inoue, D.; Asada, S.; Yamasaki, S.; Matsumoto, A.; Yamaguchi, K.; Isobe, Y.; Tsuchiya, A.; Shikata, S.; Sato, N.; Morinaga, H.; Fukuyama, T.; Tanaka, Y.; Fukushima, T.; Takeda, R.; Yamamoto, K.; Honda, H.; Nishimura, E. K.; Furukawa, Y.; Shibata, T.; Abdel-Wahab, O.; Suematsu, M.; Kitamura, T.
Article Title: Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
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. © 2021, The Author(s).
Keywords: signal transduction; protein kinase b; aged; genetics; mutation; cell proliferation; mouse; phenotype; animal; metabolism; animals; mice; dna damage; cells, cultured; cell cycle; apoptosis; gene expression; protein; mitochondrial membrane potential; hematopoietic stem cell transplantation; drug effect; inhibitor; physiology; transgenic mouse; mice, transgenic; dna; ubiquitination; cell culture; tumor suppressor proteins; proto-oncogene proteins c-akt; hematopoietic stem cells; reactive oxygen species; reactive oxygen metabolite; hematopoiesis; aging; hematopoietic stem cell; gene knock-in techniques; tumor suppressor protein; repressor protein; repressor proteins; rapamycin; membrane potential, mitochondrial; sirolimus; ubiquitin thiolesterase; cell; tor serine-threonine kinases; target of rapamycin kinase; rna-seq; detection method; clonal hematopoiesis; cell component; humans; human; induced response; gene knock-in; asxl1 protein, mouse; bap1 protein, mouse
Journal Title: Nature Communications
Volume: 12
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2021-03-23
Start Page: 1826
Language: English
DOI: 10.1038/s41467-021-22053-y
PUBMED: 33758188
PROVIDER: scopus
PMCID: PMC7988019
Notes: Article -- Export Date: 3 May 2021 -- Source: Scopus
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MSK Authors
  1. Daichi   Inoue
    27 Inoue