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Identification of novel targets for leukemia therapy using genome-wide CRISPR/Cas9 screens

Research Project

Project/Area Number 17H01567
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKyushu University

Principal Investigator

Takahiro Maeda  九州大学, 大学病院, 准教授 (00791972)

Co-Investigator(Kenkyū-buntansha) 山内 拓司  九州大学, 大学病院, 助教 (20796213)
菊繁 吉謙  九州大学, 医学研究院, 講師 (40619706)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2019: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
Fiscal Year 2018: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000)
Fiscal Year 2017: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
Keywords急性骨髄性白血病 / 白血病 / CRISPR / DCPS / PAICS / AML / CRISPR/Cas9スクリーニング / CRISPR/Cas9 / 分化誘導療法 / プレmRNAプロセッシング / ゲノム編集
Outline of Final Research Achievements

Acute Myeloid leukemia (AML) is a devastating disease with a long-term survival rate of less than 30%. To identify novel targets for AML therapy, we performed genome-wide CRISPR/Cas9 screens using mouse AML lines that we generated. We identified DCPS (recapping enzyme scavenger) as a novel target for AML therapy. RG3039, a DCPS inhibitor, exhibited anti-AML activity both in vitro (AML cell lines) and in vivo (patient-derived mouse AML models) (Yamauchi et al. Cancer Cell, 2018). We also identified other targets for AML therapy from those screens. We presented a part of our findings at the 2019 ASH annual meeting, and a paper related to this project is currently under review.

Academic Significance and Societal Importance of the Research Achievements

近年のがんゲノム解析技術の進歩により、急性骨髄性白血病(AML)の発症に関わる遺伝子異常はほぼ解明されたが、どの遺伝子が実際に治療標的になるかは不明な点が多い。我々の研究の特徴および新規性は、AML細胞の分化、細胞死といった表現型を指標に、ヒトの全遺伝子の一つ一つを標的に、盲目的、かつ網羅的にAML細胞の生存に必要な遺伝子の同定を探索したことである。結果として、DCPS分子をはじめとした、過去のの手法では発見し得なかった新たな治療標的を複数同定したことに、本研究の意義がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (30 results)

All 2019 2018 2017 Other

All Int'l Joint Research (7 results) Journal Article (7 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 6 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (14 results) (of which Int'l Joint Research: 12 results,  Invited: 2 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Int'l Joint Research] Harvard University/Broad Institute(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] LifeArc(英国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Harvard University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Harvard Medical School/Brigham and Women's Hospital/Boston Children’s Hospital(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Dana-Farber Cancer Institute/Massachusetts General Hospital(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Institute of Medical Biology(Singapore)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] 8Al-Balqa Applied University(Jordan)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Rational targeting of a NuRD subcomplex guided by comprehensive in situ mutagenesis2019

    • Author(s)
      33.Sher F, Hossain M, Seruggia D, Schoonenberg V.A.C., Yao Q, Cifani P, Dassama L.M.K., Cole MA, Ren C, Vinjamur DS, Macias-Trevino C, Luk K, McGuckin C, Schupp PG, Canver M.C., Kurita R, Nakamura Y, Fujiwara Y, Wolfe SA, Pinello L, Maeda T, Kentsis A, Orkin SH, Bauer DE.
    • Journal Title

      Nature Genetics

      Volume: 51 Issue: 7 Pages: 1149-1159

    • DOI

      10.1038/s41588-019-0453-4

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Molecular pathogenesis of disease progression in MLL-rearranged AML.2018

    • Author(s)
      Kotani S, Yoda A, Kon A, Kataoka K, Ochi Y, Shiozawa Y, Hirsch C, Takeda J, Ueno H, Yoshizato T, Yoshida K, Nakagawa MM, Nannya Y, Kakiuchi N, Yamauchi T, Aoki K, Shiraishi Y, Miyano S, Maeda T, Maciejewski JP, Takaori-Kondo A, Ogawa S, Makishima H.
    • Journal Title

      Leukemia

      Volume: 33 Issue: 3 Pages: 612-624

    • DOI

      10.1038/s41375-018-0253-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS.2018

    • Author(s)
      Sugio T, Miyawaki K, Kato K, Sasaki K, Yamada K, Iqbal J, Miyamoto T, Ohshima K, Maeda T, Miyoshi H, Akashi K.
    • Journal Title

      Blood Advances

      Volume: 2 Issue: 17 Pages: 2242-2252

    • DOI

      10.1182/bloodadvances.2018018754

    • NAID

      40021890654

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CRISPRO: identification of functional protein coding sequences based on genome editing dense mutagenesis2018

    • Author(s)
      Schoonenberg Vivien A. C.、Cole Mitchel A.、Yao Qiuming、Macias-Trevino Claudio、Sher Falak、Schupp Patrick G.、Canver Matthew C.、Maeda Takahiro、Pinello Luca、Bauer Daniel E.
    • Journal Title

      Genome Biology

      Volume: 19 Issue: 1 Pages: 00-00

    • DOI

      10.1186/s13059-018-1563-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] DrugThatGene: integrative analysis to streamline the identification of druggable genes, pathways and protein complexes from CRISPR screens2018

    • Author(s)
      Canver Matthew C、Bauer Daniel E、Maeda Takahiro、Pinello Luca
    • Journal Title

      Bioinformatics

      Volume: 5 Issue: 11 Pages: 00-00

    • DOI

      10.1093/bioinformatics/bty913

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS.2018

    • Author(s)
      Yamauchi T, et al.
    • Journal Title

      Cancer Cell.

      Volume: 33 Issue: 3 Pages: 386-400

    • DOI

      10.1016/j.ccell.2018.01.012

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of unipotent megakaryocyte progenitors in human hematopoiesis.2017

    • Author(s)
      K. Miyawaki. Iwasaki, T. Jiromaru, H. Kusumoto, A. Yurino, T. Sugio, Y. Uehara, J. Odawara, S. Daitoku, Y. Kunisaki, Y. Mori, Y. Arinobu, H. Tsuzuki, Y. Kikushige, T. Iino, K. Kato, K. Takenaka, T. Miyamoto, T. Maeda, *K. Akashi
    • Journal Title

      Blood

      Volume: 印刷中 Issue: 25 Pages: 3332-3343

    • DOI

      10.1182/blood-2016-09-741611

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] CRISPR-Cas9 screen identifies Me2, a mitochondrial malic enzyme, as a molecule relevant for MCL1 inhibitor resistance2019

    • Author(s)
      Nakao F, Yamauchi T, SembaY, Nogami J, Akashi K and Maeda T.
    • Organizer
      FASEB: The Hematologic Malignancies Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CRISPR-Cas9 screen identifies XPO7 as a novel therapeutic target for TP53-mutated AML2019

    • Author(s)
      34.SembaY, Yamauchi T, Nakao F, Nogami J, Canver MC, Pinello L, Bauer DE, Akashi K, Maeda T.
    • Organizer
      FASEB: The Hematologic Malignancies Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome-wide CRISPR screen identifies PAICS, and enzyme involved in de novo purine synthesis, as a potential target for AML therapy.2019

    • Author(s)
      Yamauchi T, Miyawaki K, Semba Y, Nakao F, Nogami J, Sugio T, Sasaki K, Canver MC, Osborne S, Pinello L, Taylor D, Bauer DR, Akashi K, Maeda T
    • Organizer
      FASEB: The Hematologic Malignancies Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CRISPR-Cas9 screen identifies XPO7 as a novel therapeutic target for TP53-mutated AML2019

    • Author(s)
      SembaY, Yamauchi T, Nakao F, Nogami J, Canver MC, Pinello L, Bauer DE, Akashi K, Maeda T.
    • Organizer
      Society of Hematologic Oncology (SOHO) 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PAICS inhibition is a potential therapeutic strategy for MYC-positive aggressive DLBCL2019

    • Author(s)
      Miyawaki K, Yamauchi T, SugioT, Sasaki K, Miyoshi H, Osborne S, Taylor D, Ohshima K, Kato K, Maeda T, Akashi K
    • Organizer
      Society of Hematologic Oncology (SOHO) 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome-wide CRISPR screen identifies PAICS, an enzyme involved in de novo purine synthesis, as a potential target for AML therapy2019

    • Author(s)
      amauchi T, Miyawaki K, Semba Y, Nakao F, Nogami J, Sugio T, Sasaki K, Canver MC, Osborne S, Pinello L, Taylor D, Bauer DR, Akashi K, Maeda T.
    • Organizer
      Society of Hematologic Oncology (SOHO) 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PAICS inhibition is a potential therapeutic strategy for MYC-positive DLBCL2019

    • Author(s)
      Miyawaki K, Yamauchi T, SugioT, Sasaki K, Miyoshi H, Osborne S, Taylor D, Ohshima K, Kato K, Maeda T, Akashi K
    • Organizer
      61th American Society of Hematology annual meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CRISPR-Cas9 screen identifies Me2, a mitochondrial malic enzyme, as a molecule relevant for MCL1 inhibitor resistance in AML.2019

    • Author(s)
      Nakao F, Yamauchi T, SembaY, Nogami J, Akashi K and Maeda T.
    • Organizer
      61th American Society of Hematology annual meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CRISPR-Cas9 screen identifies XPO7 as a potential therapeutic target for TP53-mutated AML.2019

    • Author(s)
      42.SembaY, Yamauchi T, Nakao F, Nogami J, Canver MC, Pinello L, Bauer DE, Akashi K, Maeda T.
    • Organizer
      61th American Society of Hematology annual meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PAICS, a de novo purine synthetic enzyme, is a novel target for AML therapy.2019

    • Author(s)
      Yamauchi T, Miyawaki K, Semba Y, Nakao F, Nogami J, Sugio T, Sasaki K, Canver MC, Osborne S, Pinello L, Taylor D, Bauer DR, Akashi K, Maeda T.
    • Organizer
      61th American Society of Hematology annual meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Leukemia-specific dependence on a nuclear pre-mRNA processing pathway regulated by the DCPS decapping enzyme. Novel insights into nuclear events in cancer.2018

    • Author(s)
      Takahiro Maeda
    • Organizer
      Novel insights into nuclear events in cancer, Singapore
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Identifying novel targets for leukemia therapy using the CRISPR/Cas9 gene-editing tool2018

    • Author(s)
      Takahiro Maeda
    • Organizer
      Japanese Cancer Association Annual Meeting, Osaka
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Genome-wide CRISPR/Cas9 screen reveals that the DCPS scavenger decapping enzyme is essential for AML cell survival2017

    • Author(s)
      Takuji Yamauchi
    • Organizer
      American Society of Hematology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Targeting nuclear RNA metabolic pathways for the treatment of acute myeloid leukemia2017

    • Author(s)
      Takuji Yamauchi
    • Organizer
      日本血液学会
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] Identification of 131 Acute Myeloid Leukemia (AML) essential genes2018

    • Inventor(s)
      Maeda T, Yamauchi T, MaedaM
    • Industrial Property Rights Holder
      Maeda T, Yamauchi T, MaedaM
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Acquisition Date
      2018
    • Related Report
      2017 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] DCPS as a target for Acute Myeloid Leukemia2017

    • Inventor(s)
      Maeda T, Yamauchi T, MaedaM
    • Industrial Property Rights Holder
      Maeda T, Yamauchi T, MaedaM
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Acquisition Date
      2017
    • Related Report
      2017 Annual Research Report
    • Overseas

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Published: 2017-04-28   Modified: 2022-02-28  

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