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

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. NishimuraYoichi Furukawa, Tatsuhiro Shibata, Omar Abdel-Wahab, Makoto Suematsu, Toshio Kitamura

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

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.

Original language	English
Article number	1826
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22053-y
Publication status	Published - 2021 Dec 1

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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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., ... Kitamura, T. (2021). Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway. Nature communications, 12(1), [1826]. https://doi.org/10.1038/s41467-021-22053-y

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, EK, Furukawa, Y, Shibata, T, Abdel-Wahab, O, Suematsu, M & Kitamura, T 2021, 'Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway', Nature communications, vol. 12, no. 1, 1826. https://doi.org/10.1038/s41467-021-22053-y

@article{5624d25f4a01452b947889c92706c9d2,

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.",

author = "Takeshi Fujino and Susumu Goyama and Yuki Sugiura and Daichi Inoue and Shuhei Asada and Satoshi Yamasaki and Akiko Matsumoto and Kiyoshi Yamaguchi and Yumiko Isobe and Akiho Tsuchiya and Shiori Shikata and Naru Sato and Hironobu Morinaga and Tomofusa Fukuyama and Yosuke Tanaka and Tsuyoshi Fukushima and Reina Takeda and Keita Yamamoto and Hiroaki Honda and Nishimura, {Emi K.} and Yoichi Furukawa and Tatsuhiro Shibata and Omar Abdel-Wahab and Makoto Suematsu and Toshio Kitamura",

note = "Funding Information: We thank K. Matsuda for sharing p53−/− mice, Michael D. Milsom for providing SF91-IRES-GFP and SF91-Cat/SOD2-IRES-GFP vectors, IMSUT FACS Core Laboratory for flow cytometry and Nikon Imaging Laboratory for microscopic analysis. This work was supported by Grant-in-Aid for Scientific Research (B) (No. 15H04855) (to T.K.), Grant-in-Aid for Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (No. 17H05634), The Tokyo Biochemical Research Foundation (to T.K.), Japanese Society of Hematology (to T.K.), The Japan foundation for Aging and Health (to S.G.), Suzuken Memorial Foundation (to S.G.). Infrastructure of metabolomics was partly supported by JST ERATO Suematsu Gas Biology (2010–2015) (to Y.S. and M.S.). O.A.-W. is supported by grants from a Leukemia & Lymphoma Society Specialized Center for Research award as well as funding from the Edward P. Evans MDS Foundation and the Henry & Marilun Taub Foundation. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-22053-y",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway

AU - Fujino, Takeshi

AU - Goyama, Susumu

AU - Sugiura, Yuki

AU - Inoue, Daichi

AU - Asada, Shuhei

AU - Yamasaki, Satoshi

AU - Matsumoto, Akiko

AU - Yamaguchi, Kiyoshi

AU - Isobe, Yumiko

AU - Tsuchiya, Akiho

AU - Shikata, Shiori

AU - Sato, Naru

AU - Morinaga, Hironobu

AU - Fukuyama, Tomofusa

AU - Tanaka, Yosuke

AU - Fukushima, Tsuyoshi

AU - Takeda, Reina

AU - Yamamoto, Keita

AU - Honda, Hiroaki

AU - Nishimura, Emi K.

AU - Furukawa, Yoichi

AU - Shibata, Tatsuhiro

AU - Abdel-Wahab, Omar

AU - Suematsu, Makoto

AU - Kitamura, Toshio

N1 - Funding Information: We thank K. Matsuda for sharing p53−/− mice, Michael D. Milsom for providing SF91-IRES-GFP and SF91-Cat/SOD2-IRES-GFP vectors, IMSUT FACS Core Laboratory for flow cytometry and Nikon Imaging Laboratory for microscopic analysis. This work was supported by Grant-in-Aid for Scientific Research (B) (No. 15H04855) (to T.K.), Grant-in-Aid for Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (No. 17H05634), The Tokyo Biochemical Research Foundation (to T.K.), Japanese Society of Hematology (to T.K.), The Japan foundation for Aging and Health (to S.G.), Suzuken Memorial Foundation (to S.G.). Infrastructure of metabolomics was partly supported by JST ERATO Suematsu Gas Biology (2010–2015) (to Y.S. and M.S.). O.A.-W. is supported by grants from a Leukemia & Lymphoma Society Specialized Center for Research award as well as funding from the Edward P. Evans MDS Foundation and the Henry & Marilun Taub Foundation. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-021-22053-y

DO - 10.1038/s41467-021-22053-y

M3 - Article

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AN - SCOPUS:85103152867

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1826

ER -

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

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