Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22053-y
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Funding
- Tokyo Biochemical Research Foundation
- Japanese Society of Hematology
- Japan foundation for Aging and Health
- Suzuken Memorial Foundation
- JST ERATO Suematsu Gas Biology (2010-2015)
- Leukemia & Lymphoma Society Specialized Center for Research award
- Edward P. Evans MDS Foundation
- Henry & Marilun Taub Foundation
- [15H04855]
- [17H05634]
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ASXL1 mutations are frequently detected in age-related clonal hematopoiesis (CH), but their mechanism in driving CH remains unclear. The study demonstrates that expression of C-terminal truncated ASXL1 in hematopoietic stem cells leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
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. ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
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