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Identification of human acute leukemia specific metabolic pathways

Research Project

Project/Area Number 19H03687
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKyushu University

Principal Investigator

Kikushige Yoshikane  九州大学, 大学病院, 講師 (40619706)

Co-Investigator(Kenkyū-buntansha) 赤司 浩一  九州大学, 医学研究院, 教授 (80380385)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords白血病幹細胞 / がん代謝 / 代謝 / ミトコンドリア / アミノ酸代謝
Outline of Research at the Start

ヒト急性骨髄性白血病(AML)および急性リンパ球性白血病(ALL)に共通する白血病幹細胞性維持機構として、腫瘍特異的代謝特性に着目して研究を行う。先行研究において、ヒト正常および悪性造血幹細胞のメタボロームデータベースの構築に取り組んでおり本研究においても、さらに症例数を増加させてデータベースの拡充を行う。さらにこれらのデータベースより、すでにAMLとALLに共通する代謝特性として、分岐鎖アミノ酸(BCAA)代謝経路の恒常的活性化を見出しており、本研究計画においてその幹細胞性維持制御機構について解析を行うことで、新規の白血病幹細胞特異的な代謝特性を標的とした新規治療法の確立を目指す。

Outline of Final Research Achievements

In the current study, we explored the critical metabolic mechanisms underlying the maintenance of stem cell properties in human acute leukemia. Through the analysis of metabolome data sets we have established, we found that human CD34+ acute leukemia cells exhibited significantly higher cellular content of branched chain amino acids (BCAAs) as compared to normal CD34+ hematopoietic stem progenitor cells. Inhibition of BCAA metabolism strongly impaired the maintenance of leukemic stem cell properties of human acute leukemia in the xenograft models. Furthermore, we explored the molecular machineries how BCAA metabolism regulate the stemness of human acute leukemia and demonstrated that BCAA metabolism is specifically required to maintain PRC2 components including EZH2 and EED. Thus, BCAA metabolism represents a specific regulator of stem cell properties via maintaining PRC2 function in human acute leukemia.

Academic Significance and Societal Importance of the Research Achievements

本研究の遂行により、ヒト急性白血病における幹細胞性維持にとって重要な代謝特性としてBCAA代謝経路を同定することができた。また、BCAA代謝が利用する幹細胞性維持機構として、下流のPRC2機能制御を同定することができた。これらの結果から、BCAA代謝経路を標的としたヒト急性白血病における治療戦略を構築する上で、基盤的な特性を明らかにすることができた。したがって本研究の果たした意義は基礎的研究分野のみならず、今後の応用も含めた発展性のある内容であり、社会的意義も高いものであると考える。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (21 results)

All 2022 2021 2020 2019

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 8 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 10 results)

  • [Journal Article] Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions2022

    • Author(s)
      Ito Mamoru、Nakano Michitaka、Ariyama Hiroshi、Yamaguchi Kyoko、Tanaka Risa、Semba Yuichiro、Sugio Takeshi、Miyawaki Kohta、Kikushige Yoshikane、Mizuno Shinichi、Isobe Taichi、Tanoue Kenro、Taguchi Ryosuke、Ueno Shohei、Kawano Takahito、Murata Masaharu、Baba Eishi、Akashi Koichi
    • Journal Title

      Cancer Letters

      Volume: 532 Pages: 215597-215597

    • DOI

      10.1016/j.canlet.2022.215597

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TET2 Clonal Hematopoiesis Is Associated With Anthracycline-Induced Cardiotoxicity in Patients With Lymphoma2022

    • Author(s)
      Hatakeyama Kiwamu、Hieda Michinari、Semba Yuichiro、Moriyama Shohei、Wang Yuqing、Maeda Takahiro、Kato Koji、Miyamoto Toshihiro、Akashi Koichi、Kikushige Yoshikane
    • Journal Title

      JACC: CardioOncology

      Volume: 4 Issue: 1 Pages: 141-143

    • DOI

      10.1016/j.jaccao.2022.01.098

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022

    • Author(s)
      Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
    • Journal Title

      Blood Adv.

      Volume: 6 Issue: 7 Pages: 2388-2402

    • DOI

      10.1182/bloodadvances.2021004618

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Granulocyte collection by polymorphonuclear cell-targeting apheresis with medium-molecular-weight hydroxyethyl starch2021

    • Author(s)
      Henzan Tomoko、Yamauchi Takuji、Yamanaka Ikumi、Sakoda Teppei、Semba Yuichiro、Hayashi Masayasu、Kikushige Yoshikane、Mishima Hiroyuki、Ishimura Masataka、Koga Yuhki、Miyamoto Toshihiro、Ohga Shouichi、Akashi Koichi、Maeda Takahiro、Kunisaki Yuya
    • Journal Title

      International Journal of Hematology

      Volume: 114 Issue: 6 Pages: 691-700

    • DOI

      10.1007/s12185-021-03207-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TIM‐3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways2021

    • Author(s)
      Kikushige Yoshikane
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 9 Pages: 3419-3426

    • DOI

      10.1111/cas.15042

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies2020

    • Author(s)
      Kikushige Yoshikane
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 60 Issue: 4 Pages: 146-158

    • DOI

      10.3960/jslrt.20036

    • NAID

      130007955997

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Aromatase is a novel neo-substrate of cereblon responsible for immunomodulatory drugs-induced thrombocytopenia. Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D, Irifune H, Shima T, Kato K, Maeda T, Ito T, Handa H, Akashi K, Kikushige Y.2020

    • Author(s)
      Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D, Irifune H, Shima T, Kato K, Maeda T, Ito T, Handa H, Akashi K, Kikushige Y.
    • Journal Title

      Blood.

      Volume: - Issue: 24 Pages: 2146-2158

    • DOI

      10.1182/blood.2019003749

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of a human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells2020

    • Author(s)
      Jinnouchi Fumiaki、Yamauchi Takuji、Yurino Ayano、Nunomura Takuya、Nakano Michitaka、Iwamoto Chika、Obara Teppei、Miyawaki Kohta、Kikushige Yoshikane、Kato Koji、Maeda Takahiro、Miyamoto Toshihiro、Baba Eishi、Akashi Koichi、Takenaka Katsuto
    • Journal Title

      Blood

      Volume: - Issue: 19 Pages: 1661-1672

    • DOI

      10.1182/blood.2019002194

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation of a novel CD30 + B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis2020

    • Author(s)
      Higashioka K, Kikushige Y, Ayano M, Kimoto Y, Mitoma H, Kikukawa M, Akahoshi M, Arinobu Y, Horiuchi T, Akashi K, Niiro H.
    • Journal Title

      Clin Exp Immunol.

      Volume: 201 Issue: 3 Pages: 233-243

    • DOI

      10.1111/cei.13477

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TKIs induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase Ⅱ on genomic BCR-ABL.2020

    • Author(s)
      Yuda J, Odawara J, Minami M, Muta T, Kohno K, Tanimoto K, Eto T, Shima T, Kikushige Y, Kato K, Takenaka K, Iwasaki H, Minami Y, Ohkawa Y, Akashi K, Miyamoto T.
    • Journal Title

      Cancer Sci

      Volume: 111 Issue: 7 Pages: 2361-2373

    • DOI

      10.1111/cas.14424

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-GPRC5D/CD3 Bispecific T-Cell-Redirecting Antibody for the Treatment of Multiple Myeloma.2019

    • Author(s)
      Kodama T, Kochi Y, Nakai W, Mizuno H, Baba T, Habu K, Sawada N, Tsunoda H, Shima T, Miyawaki K, Kikushige Y, Mori Y, Miyamoto T, Maeda T, Akashi K.
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: 18 Issue: 9 Pages: 1555-1564

    • DOI

      10.1158/1535-7163.mct-18-1216

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] ヒト急性白血病における幹細胞性維持機構としての分岐鎖アミノ酸代謝経路2021

    • Author(s)
      菊繁吉謙
    • Organizer
      第44回分子生物学会 ワークショップ
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Identification of the enhanced lipid metabolism pathway in leukemic stem cells2021

    • Author(s)
      菊繁吉謙
    • Organizer
      第80回日本癌学会学術総会 コアシンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Evaluation of residual TIM-3+ LSC is a promising approach to predict the clinical outcome of allo-SCT2020

    • Author(s)
      Yoshikane Kikushige, Koichi Akashi
    • Organizer
      25th Congress of European Hematology Association, EHA-JSH joint symposium
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Stem Cells in Acute Myeloid Leukemia2020

    • Author(s)
      Yoshikane Kikushige, Koichi Akashi
    • Organizer
      11th Eurasian Hematology-Oncology Congress, EHOG-JSH joint symposium
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Identification of BCAAs metabolism pathway as a critical metabolic machinery for the maintenance of human acute leukemia-initiating cells2020

    • Author(s)
      菊繁吉謙 赤司浩一
    • Organizer
      第82回日本血液学会学術集会 シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ヒト急性白血病に共通する幹細胞性維持機構としてのアミノ酸代謝経路の解明2020

    • Author(s)
      菊繁吉謙 赤司浩一
    • Organizer
      第93回日本生化学学会 シンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Identification of BCAAs metabolism pathway as a critical metabolic machinery for the maintenance of human acute leukemia-initiating cells2020

    • Author(s)
      菊繁吉謙 赤司浩一
    • Organizer
      第79回日本癌学会学術総会 コアシンポジウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ヒト急性白血病幹細胞における幹細胞性維持機構としての代謝特性の解明2019

    • Author(s)
      菊繁吉謙
    • Organizer
      第1回日本医学連合 若手リトリート
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Identification of BCAAs metabolism pathway as a critical metabolic machinery for the maintenance of human acute leukemia-initiating cells2019

    • Author(s)
      菊繁吉謙
    • Organizer
      第81回日本血液学会学術集会 プレナリーセッション
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ヒト急性白血病幹細胞における幹細胞性維持機構としての代謝特性の解明2019

    • Author(s)
      菊繁吉謙
    • Organizer
      第42回分子生物学会 ワークショップ
    • Related Report
      2019 Annual Research Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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