Role of metabolic regulation in leukemia stem cells

• Project/Area Number: 15K19548
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: Ohta Kumiko 金沢大学, がん進展制御研究所, 博士研究員 (30416177)
• Research Collaborator: HIRAO ATSUSHI 金沢大学, がん進展制御研究所, 教授 (90343350)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 白血病 / FOXO / 細胞分化 / 解糖系 / 白血病幹細胞 / 栄養源シグナル / 未分化性維持 / 栄養源代謝

Outline of Final Research Achievements

Myeloid leukemias are essentially hematopoiesis gone awry at hematopoietic stem cells(HSCs)/progenitor cells. Forkhead members of the class O transcription factor (FOXO), plays a critical role of maintenance of HSCs, leukemia initiating cells. In this study, we attempted to establish a system for identification of molecules regulating differentiation blockade of leukemia stem cells by monitoring FOXO activity. Analysis of effects of the pharmaceutical inactivation of FOXO on leukemia differentiation revealed unique FOXO function in maintaining LSCs and coupling it with cellular metabolism. FOXO inhibition induced glycolysis and consequently increased apoptosis and cell differentiation, thereby suppressing tumor formation in vivo. These results indicate that FOXO is involved in metabolic reprograming and differentiation in LSCs, and thus is a promising target for leukemia.

Research Products

• [Journal Article] Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance. (2016)
  • Author(s): Hegazy AM, Yamada D, Kobayashi M, Kohno S, Ueno M, Ali MA, Ohta K, Tadokoro Y, Ino Y, Todo T, Soga T, Takahashi C, Hirao A.
  • Journal Title: J Biol Chem. Volume: 291 Issue: 41 Pages: 21496-21509
  • DOI: 10.1074/jbc.m116.734756
  • Peer Reviewed / Open Access
• [Journal Article] Foxo3a Inhibitors of Microbial Origin, JBIR-141 and JBIR-142 (2015)
  • Author(s): Teppei Kawahara, Noritaka Kagaya, Yuichi Masuda, Takayuki Doi, Miho Izumikawa, Kumiko Ohta, Atsushi Hirao, Kazuo Shin-ya
  • Journal Title: Organic letters Volume: 17 Issue: 21 Pages: 5476-5479
  • DOI: 10.1021/acs.orglett.5b02842
  • Peer Reviewed / Open Access
• [Journal Article] Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-high and CD133-low glioblastoma initiating cells. (2015)
  • Author(s): Tanaka S, Nakada M, Yamada D, Nakano I, Todo T, Ino Y, Hoshii T, Tadokoro Y, Ohta K, Ali MA, Hayashi Y, Hamada J, Hirao A.
  • Journal Title: J Neurooncol. Volume: 121 Issue: 2 Pages: 239-50
  • DOI: 10.1007/s11060-014-1630-z
  • Peer Reviewed / Open Access
• [Presentation] Role of FOXO on metabolic regulation in acute myeloid leukemia (2015)
  • Author(s): Kumiko Ohta, Kyoko Fuse, Mayasa Ueno, Kohno, Takahashi and Atsushi Hirao
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋／名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] フォークヘッド転写因子FOXOによる急性骨髄性白血病代謝調節機構 (2015)
  • Author(s): 大田久美子、布施香子、上野将也、河野晋、高橋智聡、平尾敦
  • Organizer: 第３回がんと代謝研究会
  • Place of Presentation: 金沢／石川県立音楽堂交流ホール
  • Year and Date: 2015-07-16