Identification of novel targets for leukemia therapy using genome-wide CRISPR/Cas9 screens
Project/Area Number |
17H01567
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Hematology
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Research Institution | Kyushu University |
Principal Investigator |
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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)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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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)
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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.
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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。
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Report
(4 results)
Research Products
(30 results)
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[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.
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Journal Title
Nature Genetics
Volume: 51
Issue: 7
Pages: 1149-1159
DOI
Related Report
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[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.
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Journal Title
Leukemia
Volume: 33
Issue: 3
Pages: 612-624
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Blood Advances
Volume: 2
Issue: 17
Pages: 2242-2252
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Blood
Volume: 印刷中
Issue: 25
Pages: 3332-3343
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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