Understanding of the regulation mechanisms of therapy resistance by mTOR complex 2

• Project/Area Number: 17K09919
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: Ueno Masaya 金沢大学, がん進展制御研究所, 助教 (20334766)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 抗がん剤耐性 / 白血病 / 白血病幹細胞 / 薬剤耐性 / 癌 / 治療耐性

Outline of Final Research Achievements

In order to develop therapeutic methods for cure of leukemia, it is necessary to know the characteristics of leukemia stem cells and identify the important molecules that regulate them. Previously, we studied about the regulation of metabolisms in leukemia stem cells, and we found that mTOR complex 2 (mTORC2) is important for the resistance of leukemia stem cells to anticancer drugs. A functional screening using a CRISPR custom library targeting downstream molecules of mTORC2 revealed that lipid and methionine metabolism are important for anticancer drug resistance in leukemia cells.

Academic Significance and Societal Importance of the Research Achievements

白血病の根治を目指した治療法の開発には、白血病細胞の特性を知り、その制御を司る重要な分子を特定することが必要である。研究代表者らは、白血病細胞の代謝調節に着目し研究を進め、脂質代謝経路およびメチオニン代謝経路が白血病細胞の抗がん剤耐性に重要であることを明らかにした。これらの知見は、代謝経路の阻害剤と抗がん剤を組み合わせた新たな治療法の確立に貢献することが期待される。

Research Products

• [Journal Article] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress (2018)
  • Author(s): Tadokoro Yuko、Hoshii Takayuki、Yamazaki Satoshi、Eto Koji、Ema Hideo、Kobayashi Masahiko、Ueno Masaya、Ohta Kumiko、Arai Yuriko、Hara Eiji、Harada Kenichi、Oshima Masanobu、Oshima Hiroko、Arai Fumio、Yoshimura Akihiko、Nakauchi Hiromitsu、Hirao Atsushi
  • Journal Title: Cell Stem Cell Volume: 22 Issue: 5 Pages: 713-725
  • DOI: 10.1016/j.stem.2018.04.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas. (2018)
  • Author(s): Vu HT, Kobayashi M, Hegazy AM, Tadokoro Y, Ueno M, Kasahara A, Takase Y, Nomura N, Peng H, Ito C, Ino Y, Todo T, Nakada M, Hirao A
  • Journal Title: Cancer Science Volume: 109 Issue: 8 Pages: 2497-2508
  • DOI: 10.1111/cas.13695
  • Peer Reviewed / Open Access
• [Journal Article] Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells (2018)
  • Author(s): Hui Peng, Atsuo Kasada, Masaya Ueno, Takayuki Hoshii, Yuko Tadokoro, Naho Nomura, Chiaki Ito, Yusuke Takase, Ha Thi Vu, Masahiko Kobayashi, Bo Xiao, Paul F. Worley, Atsushi Hirao
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 1 Pages: 1129-1135
  • DOI: 10.1016/j.bbrc.2017.11.140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression (2017)
  • Author(s): Ali Mohamed A. E.、Fuse Kyoko、Tadokoro Yuko、Hoshii Takayuki、Ueno Masaya、Kobayashi Masahiko、Nomura Naho、Vu Ha Thi、Peng Hui、Hegazy Ahmed M.、Masuko Masayoshi、Sone Hirohito、Arai Fumio、Tajima Atsushi、Hirao Atsushi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11442-11442
  • DOI: 10.1038/s41598-017-11909-3
  • Peer Reviewed / Open Access
• [Presentation] Identification of FOXOs-mediated differentiation block pathway in LSCs (2019)
  • Author(s): Ueno M, Takase Y, Kurayoshi K, Ohta K, Fuse K, Nishida Y, Kojima K, Hirao A
  • Organizer: 日本血液学会
• [Presentation] mTORC2-mediated metabolic processes contributes drug resistance in leukemia (2018)
  • Author(s): Ueno M, Hirao A
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] mTORC2-mediated metabolic processes contributes drug resistance in leukemia (2018)
  • Author(s): Ueno M, Hirao A
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Rhebの欠損はT-ALLの発症を抑制するが、正常造血に影響を及ぼさない (2017)
  • Author(s): 上野将也, 彭 卉, 笠田篤郎, 星居孝之, 平尾敦
  • Organizer: 日本血液学会学術集会
• [Presentation] Rhebの欠損はT-ALLの発症を抑制するが、正常造血に影響しない (2017)
  • Author(s): 上野将也, 河野晋, 西村建徳, 後藤典子, 髙橋 智聡 , 平尾敦
  • Organizer: 日本癌学会学術総会