• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Development of Novel Therapies for Refractory Leukemia Based on Mechanistic Insights

Research Project

Project/Area Number 21H04805
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Kurokawa Mineo  東京大学, 医学部附属病院, 教授 (80312320)

Project Period (FY) 2021-04-05 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥42,380,000 (Direct Cost: ¥32,600,000、Indirect Cost: ¥9,780,000)
Fiscal Year 2023: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2022: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2021: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Keywords難治性白血病 / EVI1 / 腫瘍免疫 / マウスモデル / CCND1 / 急性骨髄性白血病 / 骨髄異形成症候群 / 白血病 / HMGA1 / 疾患モデルマウス / 治療抵抗性白血病
Outline of Research at the Start

難治性白血病の治療開発では、遺伝子異常の同定に加え、エピジェネティクス、代謝、骨髄造血環境など、難治性病態を形成する異常の相互作用を適切なモデルを用いて明らかにし、治療標的化する必要がある。本研究は(1)最も難治性の白血病サブタイプであるEVI1高発現白血病の発症・難治化機構の解明と新規治療法の開発、(2) 骨髄異形成症候群から続発する白血病の難治性機序の解明、(3) エピジェネティクス異常を有する白血病特異的な治療標的の同定、 (4) 再発難治症例検体の単一細胞解析に基づく難治性機序の解明、を中心に、疾難治性白血病の病態解明と治療標的の探索を行い、難治性白血病の新規治療開発の基盤を確立する。

Outline of Final Research Achievements

We conducted a detailed analysis of the significance of the CCND1 and IFN-γ pathways in a mouse model of difficult-to-treat leukemia with high expression of EVI1. We found that inhibition of CCND1 suppresses proliferation in EVI1-high leukemia, with a more pronounced effect observed in vivo compared to in vitro. Inhibition of CCND1 led to decreased expression of genes involved in chemokine production and interferon response, as well as decreased expression of PD-L1 in EVI1-high leukemia cells. Mice with EVI1-high leukemia treated with inhibitors of CCND1, interferon-gamma receptor, and the downstream signaling hub molecule STAT1 showed delayed onset of the disease. Infiltrating T cells in the spleens of these mice showed reduced exhaustion markers. Combined with the detailed analysis on the related chemokine, our observation indicate that the CCND1-IFN-γ-STAT1 axis contributes to the refractory nature of EVI1-high leukemia via T cell exhaustion.

Academic Significance and Societal Importance of the Research Achievements

我々は CCND1-IFN-γ-STAT1軸の異常 が腫瘍免疫の異常を誘導しており、これがEVI1高発現白血病の治療標的となりうることを見出した。今後はIFN-γ、IFN-γ受容体、STAT1などの欠失マウスを用いて、EVI1高発現白血病をはじめとする難治性白血病における同様の腫瘍免疫の異常が広く急性骨髄性白血病の治療標的となるか検証を行う。本治療戦略が有効な白血病サブタイプの同定を行い、急性骨髄性白血病の新たな治療法の確立を目指す。本研究成果は将来的に、予後不良の難治生白血病患者に対する全く新しい治療法の開発のための基礎的知見の集積に大きく貢献するものである。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Comments on the Screening Results   Annual Research Report
  • Research Products

    (25 results)

All 2024 2023 2022 2021

All Journal Article (11 results) (of which Peer Reviewed: 9 results,  Open Access: 7 results) Presentation (14 results) (of which Int'l Joint Research: 7 results)

  • [Journal Article] Recurrent DDX41 mutation in very late relapse after allogeneic stem cell transplantation2024

    • Author(s)
      Kambara Yasuhiro、Sadato Daichi、Toya Takashi、Honda Akira、Kato Seiko、Hirama Chizuko、Haraguchi Kyoko、Shimizu Hiroaki、Najima Yuho、Kobayashi Takeshi、Okuyama Yoshiki、Harada Hironori、Takahashi Satoshi、Kurokawa Mineo、Harada Yuka、Doki Noriko
    • Journal Title

      Leukemia

      Volume: 38 Issue: 3 Pages: 667-670

    • DOI

      10.1038/s41375-024-02152-7

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] AKT2 inhibition accelerates the acquisition of phagocytic ability in induced pluripotent stem cell?derived neutrophils2024

    • Author(s)
      Hino Toshiya、Nakahara Fumio、Miyauchi Masashi、Ito Yusuke、Masamoto Yosuke、Morita Ken、Kagoya Yuki、Kojima Hirotatsu、Kurokawa Mineo
    • Journal Title

      Experimental Hematology

      Volume: 130 Pages: 104137-104137

    • DOI

      10.1016/j.exphem.2023.104137

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX412023

    • Author(s)
      Homan Claire C.、Drazer Michael W.、Yu Kai、Lawrence David M.、Feng Jinghua、Arriola-Martinez Luis、Pozsgai Matthew J.、McNeely Kelsey E.、Ha Thuong、Venugopal Parvathy、Arts Peer、King-Smith Sarah L.、...、Kurokawa Mineo et al.
    • Journal Title

      Blood Advances

      Volume: 7 Issue: 20 Pages: 6092-6107

    • DOI

      10.1182/bloodadvances.2023010045

    • 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
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] CCDC88C-FLT3 gene fusion in CD34-positive haematopoietic stem and multilineage cells in myeloid/lymphoid neoplasm with eosinophilia.2022

    • Author(s)
      Kurihara Y, Mizuno H, Honda A, Shimura A, Fujioka Y, Maki H, Kurokawa M.
    • Journal Title

      Journal of cellular and molecular medicine

      Volume: 26 Issue: 3 Pages: 950-952

    • DOI

      10.1111/jcmm.17143

    • 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
  • [Journal Article] Efficient production of human neutrophils from iPSCs that prevent murine lethal infection with immune cell recruitment.2021

    • Author(s)
      Miyauchi M, Ito Y, Nakahara F, Hino T, Nakamura F, Iwasaki Y, Kawagoshi T, Koya J, Yoshimi A, Arai S, Kagoya Y, Kurokawa M
    • Journal Title

      Blood

      Volume: 138 Issue: 24 Pages: 2555-2569

    • DOI

      10.1182/blood.2021011576

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia.2021

    • Author(s)
      Honda A, Koya J, Yoshimi A, Miyauchi M, Taoka K, Kataoka K, Arai S, Kurokawa M.
    • Journal Title

      Experimental Hematology

      Volume: - Pages: 42-48.e11

    • DOI

      10.1016/j.exphem.2021.07.005

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Physical interaction between BAALC and DBN1 induces chemoresistance in leukemia2021

    • Author(s)
      Maki Hiroaki、Yoshimi Akihide、Shimada Takashi、Arai Shunya、Morita Ken、Kamikubo Yasuhiko、 Ikegawa Masaya、Kurokawa Mineo
    • Journal Title

      Experimental Hematology

      Volume: 94 Pages: 31-36

    • DOI

      10.1016/j.exphem.2020.12.003

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Genome-wide screen in myeloid leukemia cells identified novel regulatory factors of the EVI1 gene.2023

    • Author(s)
      林田裕樹、正本庸介、日野俊哉、森田剣、黒川峰夫
    • Organizer
      第85回 日本血液学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Genome-wide screen in myeloid leukemia cell lines identifies novel upstream regulatory factors of the EVI1 gene.2023

    • Author(s)
      Hiroki Hayashida, Yosuke Masamoto, Toshiya Hino, Ken Morita, Mineo Kurokawa
    • Organizer
      第82回 日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Genome-wide screen in myeloid leukemia cell lines identifies novel upstream regulatory factors of the EVI1 gene.2023

    • Author(s)
      Hiroki Hayashida, Yosuke Masamoto, Toshiya Hino, Ken Morita, Mineo Kurokawa
    • Organizer
      第20回 幹細胞シンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] Identification of ZFP91 As the Master Transcription Factor for EVI1 Gene Expression2023

    • Author(s)
      Hiroki Hayashida, Yosuke Masamoto, Toshiya Hino, Ken Morita, Mineo Kurokawa
    • Organizer
      65th ASH Annual Meeting & Exposition
    • Related Report
      2023 Annual Research Report
  • [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
      64th ASH annual meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cooperative inhibitory effect of IDH1 mutation and ASXL1 mutation on normal myeloid differentiation2022

    • Author(s)
      Masami Ohzu, Kazutoshi Ebisawa, Ken Morita, Yosuke Masamoto, Mineo Kurokawa
    • Organizer
      64th ASH annual meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Interactions between eIF4B and CAMK2G promote proliferation of malignant cells in myelofibrosis2022

    • Author(s)
      Ken Sasaki, Tadayuki Ogawa, Yosuke Masamoto, Hideaki Mizuno, Mineo Kurokawa
    • Organizer
      第45回 日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] EVI1はAMLマウスモデルでcyclinD1を介して免疫回避的な微小環境を形成する2022

    • Author(s)
      正本庸介、千葉晶輝、水野秀明、日野俊哉、林田裕樹、黒川峰夫
    • Organizer
      第84回 日本血液学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] eIF4BはCAMK2Gと相互作用し、骨髄線維症の進展に寄与する2022

    • Author(s)
      佐々木謙、小川覚之、正本庸介、水野秀明、黒川峰夫
    • Organizer
      第84回 日本血液学会学術総会
    • 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, Hiroki Hayashida, Hideaki Mizuno, Tomohiko Sato, Mineo Kurokawa
    • Organizer
      63rd ASH annual meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intrapatient Complex Transcriptional Responses to Conventional Chemotherapy in Relapsed Acute Myeloid Leukemia Revealed By Single Cell RNA-Seq Analysis2021

    • Author(s)
      Hideaki Mizuno, Akira Honda, Mineo Kurokawa
    • Organizer
      63rd ASH annual meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] eIF4B is a novel target of CAMK2G and promotes proliferation of malignant cells in myelofibrosis2021

    • Author(s)
      Ken Sasaki, Tadayuki Ogawa, Hideaki Mizuno, Mineo Kurokawa
    • Organizer
      63rd ASH annual meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] シングルセルRNAシークエンスに基づくAMLの治療反応の多様性2021

    • Author(s)
      水野秀明、本田晃、黒川峰夫
    • Organizer
      第83回 日本血液学会学術総会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 正常造血においてGFI1はEVI1の下流標的である2021

    • Author(s)
      千葉晶輝、正本庸介、水野秀明、黒川峰夫
    • Organizer
      第83回 日本血液学会学術総会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi