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

Autor: Fujino T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Goyama S; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Sugiura Y; Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Shinjuku-ku, Tokyo, Japan., Inoue D; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, USA.; Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe City, Hyogo, Japan., Asada S; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.; Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan., Yamasaki S; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Matsumoto A; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Yamaguchi K; Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Isobe Y; Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Tsuchiya A; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Shikata S; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Sato N; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Morinaga H; Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan., Fukuyama T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Tanaka Y; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Fukushima T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Takeda R; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Yamamoto K; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Honda H; Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan., Nishimura EK; Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan., Furukawa Y; Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Shibata T; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan., Abdel-Wahab O; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, USA., Suematsu M; Department of Biochemistry, Keio University School of Medicine, and Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Shinjuku-ku, Tokyo, Japan., Kitamura T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan. kitamura@ims.u-tokyo.ac.jp.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Mar 23; Vol. 12 (1), pp. 1826. Date of Electronic Publication: 2021 Mar 23.
DOI: 10.1038/s41467-021-22053-y
Abstrakt: 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.
Databáze: MEDLINE