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; Toshio Kitamura

doi:10.1038/s41467-021-22053-y

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

Nat Commun. 2021 Mar 23;12(1):1826. doi: 10.1038/s41467-021-22053-y.

Authors

Takeshi Fujino¹, Susumu Goyama¹, Yuki Sugiura², Daichi Inoue^{3

4}, Shuhei Asada^{1

5}, Satoshi Yamasaki⁶, Akiko Matsumoto⁶, Kiyoshi Yamaguchi⁷, Yumiko Isobe⁷, Akiho Tsuchiya¹, Shiori Shikata¹, Naru Sato¹, Hironobu Morinaga⁸, Tomofusa Fukuyama¹, Yosuke Tanaka¹, Tsuyoshi Fukushima¹, Reina Takeda¹, Keita Yamamoto¹, Hiroaki Honda⁵, Emi K Nishimura⁸, Yoichi Furukawa⁷, Tatsuhiro Shibata⁶, Omar Abdel-Wahab³, Makoto Suematsu², Toshio Kitamura⁹

Affiliations

¹ Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
² 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.
³ Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, USA.
⁴ Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe City, Hyogo, Japan.
⁵ Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
⁶ Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
⁷ Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
⁸ Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
⁹ Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aging / genetics*
Aging / metabolism
Aging / physiology
Animals
Apoptosis / genetics
Cell Cycle / genetics
Cell Proliferation / genetics
Cells, Cultured
Clonal Hematopoiesis / genetics*
DNA Damage / drug effects
DNA Damage / genetics
Gene Knock-In Techniques
Hematopoiesis / genetics*
Hematopoiesis / physiology
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / drug effects
Hematopoietic Stem Cells / metabolism*
Hematopoietic Stem Cells / physiology
Humans
Membrane Potential, Mitochondrial / drug effects
Membrane Potential, Mitochondrial / genetics
Mice
Mice, Transgenic
Mutation
Proto-Oncogene Proteins c-akt / metabolism
RNA-Seq
Reactive Oxygen Species / pharmacology
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics
Sirolimus / pharmacology
TOR Serine-Threonine Kinases / metabolism*
Tumor Suppressor Proteins / metabolism
Ubiquitin Thiolesterase / metabolism
Ubiquitination / drug effects
Ubiquitination / genetics

Substances

Asxl1 protein, mouse
BAP1 protein, mouse
Reactive Oxygen Species
Repressor Proteins
Tumor Suppressor Proteins
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Ubiquitin Thiolesterase
Sirolimus

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States