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Development of novel therapeutic strategies for therapy-refractory leukemia

Research Project

Project/Area Number 20H05699
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Review Section Broad Section I
Research InstitutionKyushu University

Principal Investigator

前田 高宏  九州大学, 医学研究院, 教授 (00791972)

Co-Investigator(Kenkyū-buntansha) 山内 拓司  九州大学, 大学病院, 助教 (20796213)
野上 順平  九州大学, 医学研究院, 助教 (60801751)
増田 豪  慶應義塾大学, 政策・メディア研究科(藤沢), 特任講師 (70383940)
仙波 雄一郎  九州大学, 医学研究院, 助教 (90816787)
Project Period (FY) 2020-08-31 – 2025-03-31
Project Status Granted (Fiscal Year 2024)
Budget Amount *help
¥196,690,000 (Direct Cost: ¥151,300,000、Indirect Cost: ¥45,390,000)
Fiscal Year 2024: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000)
Fiscal Year 2023: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000)
Fiscal Year 2022: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000)
Fiscal Year 2021: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000)
Fiscal Year 2020: ¥42,250,000 (Direct Cost: ¥32,500,000、Indirect Cost: ¥9,750,000)
Keywords急性白血病 / TP53 / p53 / 合成致死 / CRISPR / AML / ALL / BCL2 / CRSPR/Cas9 / BCL2阻害剤 / 急性骨髄性白血病 / 急性リンパ性白血病 / CRISPR/Cas9 / 機能ジェノミクス
Outline of Research at the Start

本研究の目的は、白血病難治性の分子メカニズムを解明し、新規治療法開発に向けた知見を創出することである。具体的には、機能ジェノミックス法を駆使して、3つの目的を達成する:1) 難治性を規定する遺伝子異常と合成致死関係にある遺伝子を同定し、その分子機構を解明する; 2) 薬剤耐性に関わる遺伝子や、薬剤併用療法の標的となる遺伝子を網羅的に同定し、その分子機序を解明する;3)同定分子を標的とした薬剤開発にむけた proof of concept を創出する。本研究により、難治性白血病に対する新規治療標的の同定、薬剤併用療法法の開発、白血病細胞の増殖、生存、薬剤耐性獲得に関わる分子機構の解明につながる。

Outline of Annual Research Achievements

目的1:白血病難治性を規定する遺伝子異常と合成致死関係にある遺伝子の同定とその分子機構の解明:
Trp53と合成致死関係にある遺伝子としてXpo7を同定し、Xpo7と結合し、かつXpo7の欠失によって細胞内局在が変化する因子としてNpatを同定した。Trp53欠損AML細胞でのみNpatタンパクの発現を認め、NPATがTP53変異細胞の増殖にとってbottleneckである可能性が示唆された。ヒト・マウスTP53欠損・変異AML細胞株において、dTAGによりXPO7/NPATタンパクを急性に分解させ、細胞増殖、細胞周期、アポトーシスに及ぼす影響を検討した。 次に、各種細胞株をマウスに移植し、XPO7/NPAT阻害のin vivoでの抗白血病効果を確認した。さらにヒトTP53変異AMLにおける、NPAT/XPO7の意義を、TCGA, BeatAMLのコホートで検討し、自施設検体を用いて1細胞レベルでのXPO7/NPAT発現とTP53変異状況との関連を見出した(Semba et al. under review)。IGH-CRLF2再構成ALLに対する新たな治療戦略を見出した(Sasaki et al. Blood 2022)
目的2:白血病キードラッグに対する耐性機構の解明と、新規併用療法開発に向けた標的分子の同定:
AMLにおけるVenetoclax感受性を制御する機構を見出し報告した(Nakao et al. Leukemia 2003)。ALLにおけるステロイド感受性にmTOR経路が重要であることを見出し報告した(Imanaga et al. Blood Neoplasia in press)。また、ALLにおけるSelinexor感受性に、DDXタンパクによるMCL1のmRNAの各輸送が重要であることを見出した(Terasaki et al under review)。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究課題で予定していた研究目標はほぼ達成され、関連した5報の論文発表をおこなった。
1. Yamauchi T et al. Leukemia. 2022 Feb;36(2):383-393; 2. Sasaki K et al. Blood. 2022 Feb 3 ;139(5):748-760; 3. Swartzel JC et al.ACS Chem Biol. 2022 Jul 15;17(7):1789-1798; 4. Nakao F et al. Leukemia. 2023 May;37(5):1028-1038; 5. Imanaga et al. Blood Neoplasia. in press
さらに、TP53変異AMLに対する新規治療標的に関連する論文(Semba et al)、Selinexor感受性に関する論文(Terasaki et al)が現在投稿中であり、2024年度中には論文発表する予定である。

Strategy for Future Research Activity

本研究課題では、CRISPR/Cas9全ゲノムスクリーニングを用いて、新規治療標的となりうる分子・系路の同定を行ったが、同定分子を標的とする低分子化合物の同定には到っていない。次年度は本研究課題の最終年度となるが、分子同定から創薬への道筋を探る予定である。実際、DEL (DNA encoded linrary)を使用した化合物スクリーニングを行っている。さらに、薬剤耐性の機序として、遺伝子の発現レベルの関与を継続して検討すると同時に、遺伝子欠損を伴わない細胞内の変化(エピジェネティクス、メタボロームなど)を1細胞レベルでスクリーニングする系を構築中である。

Assessment Rating
Interim Assessment Comments (Rating)

A+: In light of the aim of introducing the research area into the research categories, more progress has been made in research than expected.

Report

(6 results)
  • 2023 Annual Research Report
  • 2022 Abstract (Interim Assessment) ( PDF )   Interim Assessment (Comments) ( PDF )
  • 2020 Abstract ( PDF )   Comments on the Screening Results ( PDF )   Annual Research Report
  • Research Products

    (26 results)

All 2023 2021 2020 Other

All Int'l Joint Research (3 results) Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (12 results) (of which Int'l Joint Research: 9 results,  Invited: 8 results) Remarks (3 results)

  • [Int'l Joint Research] Harvard Medical School/Boston Children's Hospital(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Tel Aviv University/Schneider Children's Medical Center(イスラエル)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Yale University/Harvard University(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance2023

    • Author(s)
      Nakao Fumihiko、Setoguchi Kiyoko、Semba Yuichiro、Yamauchi Takuji、Nogami Jumpei、Sasaki Kensuke、Imanaga Hiroshi、Terasaki Tatsuya、Miyazaki Manaka、Hirabayashi Shigeki、Miyawaki Kohta、Kikushige Yoshikane、Masuda Takeshi、Akashi Koichi、Maeda Takahiro
    • Journal Title

      Leukemia

      Volume: - Issue: 5 Pages: 1028-1038

    • DOI

      10.1038/s41375-023-01879-z

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins2023

    • Author(s)
      Komata Yosuke、Kanai Akinori、Maeda Takahiro、Inaba Toshiya、Yokoyama Akihiko
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 1-17

    • DOI

      10.1038/s41467-023-37712-5

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CELMoD for ALL: an exciting prospect2023

    • Author(s)
      Maeda Takahiro
    • Journal Title

      Blood

      Volume: 142 Issue: 7 Pages: 614-615

    • DOI

      10.1182/blood.2023020923

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan2021

    • Author(s)
      Sunami K, Naito Y, Aimono E, Amano T, Ennishi D, Kage H, Kanai M, Komine K, Koyama T, Maeda T, Morita S, Sakai D, Kohsaka S, Tsuchihara K, Yoshino T
    • Journal Title

      Int J Clin Oncol

      Volume: 26 Issue: 3 Pages: 443-449

    • DOI

      10.1007/s10147-020-01844-1

    • Related Report
      2020 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
    • Peer Reviewed / Open Access
  • [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
    • Peer Reviewed / Open Access
  • [Journal Article] Beneficial tyrosine kinase inhibitor therapy in a patient with relapsed BCR-ABL1-like acute lymphoblastic leukemia with CCDC88C-PDGFRB fusion2020

    • Author(s)
      Oya Shuki、Morishige Satoshi、Ozawa Hidetoshi、Sasaki Kensuke、Semba Yuichiro、Yamasaki Yoshitaka、Nakamura Takayuki、Aoyama Kazutoshi、Seki Ritsuko、Mouri Fumihiko、Osaki Koichi、Miyamoto Toshihiro、Maeda Takahiro、Nagafuji Koji
    • Journal Title

      International Journal of Hematology

      Volume: 113 Issue: 2 Pages: 285-289

    • DOI

      10.1007/s12185-020-03006-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study2020

    • Author(s)
      Mori Yasuo、Fukuoka Blood and Marrow Transplantation Group、Sasaki Kensuke、Ito Yoshikiyo、Kuriyama Takuro、Ueno Toshiyuki、Kadowaki Masanori、Aoki Takatoshi、Sugio Takeshi、Yoshimoto Goichi、Kato Koji、Maeda Takahiro、Nagafuji Koji、Akashi Koichi、Miyamoto Toshihiro
    • Journal Title

      Annals of Hematology

      Volume: 100 Issue: 1 Pages: 197-208

    • DOI

      10.1007/s00277-020-04310-0

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Identifying novel targets for AML therapy using functional genomic tools.2023

    • Author(s)
      Takahiro Maeda
    • Organizer
      Japanese Society of Medical Oncology Annual meeting.
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Identifying novel targets for AML therapy using functional genomic tools.2023

    • Author(s)
      Takahiro Maeda
    • Organizer
      BMT/HM Grand Rounds, Dana-Farber Cancer Institute.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The XPO7/NPAT axis as a potential therapeutic target for TP53-mutated AML.2023

    • Author(s)
      Takahiro Maeda
    • Organizer
      FASEB Hematologic Malignancies Conference
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Harnessing functional genomics to uncover potential targets for AML therapy.2023

    • Author(s)
      Takahiro Maeda
    • Organizer
      Japanese Cancer Society annual meeting
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Multifaceted roles of the transcription factor ZBTB7A in normal and malignant hematopoiesis2023

    • Author(s)
      Takahiro Maeda
    • Organizer
      Tsuruoka Conference 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Identifying novel combination therapies for B-ALL harboring the IgH::CRLF2 rearrangement using functional genomics tools2023

    • Author(s)
      Takahiro Maeda
    • Organizer
      3rd Translational Research Conference Acute Lymphoblastic Leukaemia.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Autophagy Induction via mTORC1 Inhibition is an Essential Mechanism in Glucocorticoid-Mediated Cell Death in B-cell Precursor Acute Lymphoblastic Leukemia.2023

    • Author(s)
      Hiroshi Imanaga
    • Organizer
      FASEB Hematologic Malignancies Conference.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome-Wide CRISPR-Cas9 Screens Identify DDX19A/DDX19B As a Critical Regulator of Intrinsic Apoptosis by Regulating MCL1 mRNA Cellular Localization.2023

    • Author(s)
      Tatsuya Terasaki
    • Organizer
      FASEB Hematologic Malignancies Conference.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome-Wide CRISPR/Cas9 Screens Identify DDX19A/DDX19B As a Critical Regulator of Intrinsic Apoptosis By Regulating MCL1 mRNA Cellular Localization2023

    • Author(s)
      Tatsuya Terasaki
    • Organizer
      American Society of Hematology annual meeting, San Diego, LA, USA. 2023.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The XPO7/Npat Axis Inactivation Is a Therapeutic Vulnerability for TP53-Mutated AML2023

    • Author(s)
      Yuichiro Semba
    • Organizer
      American Society of Hematology annual meeting, San Diego, LA, USA. 2023.
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CRISPR/Cas9 遺伝子改変技術を用いた白血病治療標的分子の同定2020

    • Author(s)
      前田高宏
    • Organizer
      鶴岡カンファレンス 2020
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 白血病のクローン多様性克服に向けて2020

    • Author(s)
      前田高宏
    • Organizer
      日本造血幹細胞移植学会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 研究室ホームページ(日本語)

    • URL

      https://precision.kyushu-u.ac.jp

    • Related Report
      2023 Annual Research Report
  • [Remarks] 研究室ホームページ(英語)

    • URL

      https://precision.kyushu-u.ac.jp/en/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 九州大学大学院医学研究院プレシジョン医療学

    • URL

      https://precision.kyushu-u.ac.jp

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2020-09-07   Modified: 2024-12-25  

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