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Targeting the haematopoietic stem cell programme to understand the molecular basis of refractory acute myeloid leukaemia.

Research Project

Project/Area Number 20H03708
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 InstitutionThe University of Tokyo

Principal Investigator

MASAMOTO YOSUKE  東京大学, 医学部附属病院, 准教授 (30706974)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Keywords急性骨髄性白血病 / 白血病幹細胞
Outline of Research at the Start

急性骨髄性白血病(AML)は代表的な難治性造血器腫瘍で、高率な再発が治癒の障壁となっており、白血病幹細胞が難治化・治療抵抗性・再発の主な原因と考えられている。申請者らが作成したAML細胞は、正常造血幹細胞に類似した性質を持つ細胞であり、白血病幹細胞活性は低いものの、進行が早く化学療法抵抗性の高いAMLを起こし、ヒトにおける難治性病態のモデルになると考えられる。本研究においては、造血幹細胞様AML細胞を顆粒球・単球前駆細胞様のAML細胞や正常造血幹細胞と比較することによって、難治性AML細胞の特徴、その性質の分子基盤、治療標的を明らかにすることを目標とする。

Outline of Final Research Achievements

In the EVI1-GFP knock-in retrovirally induced MLL-ENL murine AML model, HSC-like and GMP-like AML cells were sorted by GFP expression and compared for gene expression pattern. The HSC-like AML cells induce refractory AML despite low leukemia stem cell frequency. The HSC-like AML cells were characterized by enrichment of the NF-κB pathway, chemotherapy resistance-related gene cluster, and elevated chemokine expression, consistent with the phenotype of HSC-like AML cells. The EVI1-high AML model with HSC-like expression patterns also shared the same transcriptional profile as HSC-like AML cells: the immune-related pathways, including chemokines and IFN-γ pathway, which were regulated by cyclin D1. We also demonstrated that the genetic modification of Cyclin D1, chemokine and IFN-γ pathway can suppress AML development.

Academic Significance and Societal Importance of the Research Achievements

代表的造血器腫瘍であるAMLの難治性病態を解明するため、AML幹細胞の中でも特に難治性病態に関連するHSC様AML細胞の性質の解析を行った。HSC様AML細胞は幹細胞活性の高さとは関係なく、既知の難治性関連遺伝子群の発現と関連しており、さらに面白いことに、免疫関係の遺伝子発現と関連していた。複数のAMLモデルを用いることにより、cyclin D1, ケモカイン、IFN-γ経路などがHSC様AML細胞を特徴づけることを明らかにした。またこれらの経路がHSC様AML細胞の脆弱性を構成し、治療標的になりうる可能性を提示した。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (14 results)

All 2024 2023 2022 2021 2020

All Journal Article (8 results) (of which Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (6 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Long-term remission after upfront autologous hematopoietic stem cell transplant for CD5+ diffuse large-B cell lymphoma2024

    • Author(s)
      Masamoto Y, Honda A, Shinozaki-Ushiku A, Ushiku T, Kurokawa M.
    • Journal Title

      Journal of Chemotherapy

      Volume: - Issue: 1 Pages: 85-93

    • DOI

      10.1080/1120009x.2024.2340147

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A key to engineering natural killer cells to attack acute myeloid leukemia.2024

    • Author(s)
      Masamoto Y, Kurokawa M.
    • Journal Title

      Haematologica

      Volume: 109 Pages: 1302-4

    • DOI

      10.3324/haematol.2023.284272

    • Related Report
      2023 Annual Research Report
  • [Journal Article] EVI1 exerts distinct roles in AML via ERG and cyclin D1 promoting a chemoresistant and immune-suppressive environment2023

    • Author(s)
      Masamoto Yosuke、Chiba Akira、Mizuno Hideaki、Hino Toshiya、Hayashida Hiroki、Sato Tomohiko、Bando Masashige、Shirahige Katsuhiko、Kurokawa Mineo
    • Journal Title

      Blood Advances

      Volume: 7 Issue: 8 Pages: 1577-1593

    • DOI

      10.1182/bloodadvances.2022008018

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bone marrow involvement is a risk factor for infusion-related reactions in patients with follicular lymphoma treated by obinutuzumab.2023

    • Author(s)
      Masamoto Y, Shimura A, Honda A, Taoka K, Maki H, Kurokawa M.
    • Journal Title

      Annals of Hematology

      Volume: 102(1) Issue: 1 Pages: 243-244

    • DOI

      10.1007/s00277-022-05037-w

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bone marrow involvement is a risk factor for infusion-related reactions in patients with follicular lymphoma treated by obinutuzumab.2022

    • Author(s)
      Masamoto Y, Taoka K, Maki H, Kurokawa M.
    • Journal Title

      Annals of Hematology

      Volume: 101(12) Issue: 12 Pages: 2795-2797

    • DOI

      10.1007/s00277-022-04987-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CAMK2G is identified as a novel therapeutic target for myelofibrosis.2022

    • Author(s)
      Miyauchi M, Sasaki K, Kagoya Y, Taoka K, Masamoto Y, Yamazaki S, Arai S, Mizuno H, Kurokawa M.
    • Journal Title

      Blood Advances

      Volume: 6 Issue: 5 Pages: 1585-1597

    • DOI

      10.1182/bloodadvances.2020003303

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dnmt3a R878C induces expansion of quiescent hematopoietic stem cell pool2022

    • Author(s)
      Higo T, Suzuki Y, Sato M, Koya J, Mizuno H, Miyauchi M, Masamoto Y, Kataoka K, Sumitomo Y, Tsuruta-Kishino T, Sato T, Kurokawa M.
    • Journal Title

      Experimental Hematology

      Volume: - Pages: 45-54

    • DOI

      10.1016/j.exphem.2022.02.006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation.2021

    • Author(s)
      Mizuno H, Koya J, Masamoto Y, Kagoya Y, Kurokawa M.
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 10 Pages: 4112-4126

    • DOI

      10.1111/cas.15098

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Identification of ZFP91 As the Master Transcription Factor for EVI1 Gene Expression2023

    • Author(s)
      Hiroki Hayashida, Toshiya Hino, Ken Morita, Yosuke Masamoto, and Mineo Kurokawa,
    • Organizer
      第65回米国血液学会総会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] EVI1 promotes immune-evasive microenvironment via cyclin D1 in acute myeloid leukemia2022

    • Author(s)
      Yosuke Masamoto, Akira Chiba, Toshiya Hino, Hiroki Hayashida, Hideaki Mizuno, Tomohiko Sato, Mineo Kurokawa
    • Organizer
      The 64th ASH Annual Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] EVI1 promotes immune-evasive microenvironment via cyclin D1 in acute myeloid leukemia2022

    • Author(s)
      Yosuke Masamoto, Akira Chiba, Hideaki Mizuno, Toshiya Hino Hiroki Hayashida, Mineo Kurokawa
    • Organizer
      第84回日本血液学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] EVI1 promotes immune-evasive microenvironment via cyclin D1 in acute myeloid leukemia2022

    • Author(s)
      Yosuke Masamoto, Hideaki Mizuno, Mineo Kurokawa
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] EVI1-positive AML cells show distinct features and high dependency on ETS transcription factor ERG2021

    • Author(s)
      Yosuke Masamoto, Akira Chiba, Toshiaki Takezaki, Toshiya Hino, Hiroki Hayashida, Hideaki Mizuno, Tomohiko Sato, Mineo Kurokawa
    • Organizer
      第63回アメリカ血液学会総会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] EVI1-positive AML stem cells survive cytotoxic chemotherapy and induce highly aggressive AML2020

    • Author(s)
      Yosuke Masamoto
    • Organizer
      第82回日本血液学会総会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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