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Role of S-adenosylmethionine in the Maintenance of Hematopoietic Stem and Progenitor Cells

Research Project

Project/Area Number 22K16295
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionTohoku University

Principal Investigator

Kato Hiroki  東北大学, 大学病院, 講師 (50801677)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsメチオニン代謝 / SAM / MAT2A / 遺伝子発現調節 / メチオニン / S-アデノシルメチオニン / 造血 / エピゲノム / 造血幹細胞分化
Outline of Research at the Start

S-アデノシルメチオニン(SAM)はメチオニンとATPから酵素MAT2Aにより合成される。SAMはDNAやヒストン、RNAのメチル化に必須のメチル基供与体であり、遺伝子発現の調節を介して細胞の分化制御に重要と予想される。しかし、生体内の造血におけるSAMの役割には不明な点が多い。そこで本研究では、造血細胞特異的MAT2A欠損マウスの解析を通してSAMの造血幹細胞分化での役割を解明する。メチオニン代謝は自己免疫疾患やがん、老化の治療標的としても近年注目されており、本研究は栄養の代謝が造血細胞の分化を制御する仕組みを解明するとともに、現代医療が直面する諸問題を克服する端緒になると期待される。

Outline of Final Research Achievements

In this study, we developed the drug-inducible and hematopoietic cell-specific S-adenosylmethionine (SAM) synthase knock-out mouse. We confirmed the knock-out efficiency by gene expression analysis and mass spectrometry analysis. We found that the SAM synthase knock-out induced hematopoietic stem and progenitor cell (HSPC) reduction within several days. Additional analyses revealed that cell-intrinsic SAM synthesis is inevitable for the maintenance of HSPCs. p53 pathway alteration might be involved in the loss of HSPCs induced by this SAM synthase knock-out.

Academic Significance and Societal Importance of the Research Achievements

これまで、生体内造血でのSAM合成の意義には不明な点が多かった。今回我々は、造血細胞特異的にSAM合成酵素の欠損誘導が可能なマウスを作成し、その表現型を解析した。その結果、細胞自律的なSAM合成が造血幹前駆細胞の維持に必要であることが明らかとなり、そこにp53経路活性の調整が関わる可能性を見出した。SAMは栄養のシグナルである可能性があり、栄養の供給量に応じて、細胞の数や分化が調節されている可能性が考えられ、その実現機構としてSAM代謝が進化上重要な可能性がある。SAM代謝はがんの治療標的としても近年注目されており、今後の新規治療法の開発において、今回の研究による知見が役立つと期待される。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (6 results)

All 2023 2022

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Heme-dependent induction of mitophagy program during differentiation of murine erythroid cells2023

    • Author(s)
      Ikeda Masatoshi、Kato Hiroki、Shima Hiroki、Matsumoto Mitsuyo、Furukawa Eijiro、Yan Yan、Liao Ruiqi、Xu Jian、Muto Akihiko、Fujiwara Tohru、Harigae Hideo、Bresnick Emery H.、Igarashi Kazuhiko
    • Journal Title

      Experimental Hematology

      Volume: 118 Pages: 21-30

    • DOI

      10.1016/j.exphem.2022.11.007

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Elucidation of the Role of FAM210B in Mitochondrial Metabolism and Erythropoiesis2022

    • Author(s)
      Suzuki Chie、Fujiwara Tohru、Shima Hiroki、Ono Koya、Saito Kei、Kato Hiroki、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Nakamura Yukio、Igarashi Kazuhiko、Harigae Hideo
    • Journal Title

      Molecular and Cellular Biology

      Volume: 42 Issue: 12

    • DOI

      10.1128/mcb.00143-22

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Exploring the mechanistic link between SF3B1 mutation and ring sideroblast formation in myelodysplastic syndrome2022

    • Author(s)
      Ochi Tetsuro、Fujiwara Tohru、Ono Koya、Suzuki Chie、Nikaido Maika、Inoue Daichi、Kato Hiroki、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Nakamura Yukio、Harigae Hideo
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 14562-14562

    • DOI

      10.1038/s41598-022-18921-2

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis2022

    • Author(s)
      Ono Koya、Fujiwara Tohru、Saito Kei、Nishizawa Hironari、Takahashi Noriyuki、Suzuki Chie、Ochi Tetsuro、Kato Hiroki、Ishii Yusho、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Yamada Rie、Nakamura Yukio、Igarashi Kazuhiko、Harigae Hideo
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 9024-9024

    • DOI

      10.1038/s41598-022-12940-9

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] TM5614, an Inhibitor of Plasminogen Activator Inhibitor-1, Exerts an Antitumor Effect on Chronic Myeloid Leukemia2022

    • Author(s)
      Sasaki Katsuyuki、Fujiwara Tohru、Ochi Tetsuro、Ono Koya、Kato Hiroki、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Miyata Toshio、Harigae Hideo
    • Journal Title

      The Tohoku Journal of Experimental Medicine

      Volume: 257 Issue: 3 Pages: 211-224

    • DOI

      10.1620/tjem.2022.J036

    • ISSN
      0040-8727, 1349-3329
    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] HEMATOPOIETIC STEM AND PROGENITOR CELL INTRINSIC SAM SYNTHESIS IS REQUIRED TO PREVENT P53 PATHWAY ACTIVATION BY MAINTAINING DNA STABILITY2023

    • Author(s)
      Eijiro Furukawa, Hiroki Kato, Sayaka Sano, Yan Yan, Daigo Michimata, Yuya Tanaka, Kazuki Sakurai, Koichi Onodera, Satoshi Ichikawa, Noriko Fukuhara, Yasushi Onishi, Hisayuki Yokoyama, Daisuke Saigusa, Tohru Fujiwara, Kazuhiko Igarashi, Hideo Harigae
    • Organizer
      第65回米国血液学会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2022-04-19   Modified: 2025-01-30  

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