Identification of the novel therapeutic target molecules for leukemia stem cells based on TIM-3/galectin-9 interaction

• Project/Area Number: 26713034
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: Kikushige Yoshikane 九州大学, 医学(系)研究科(研究院), 助教 (40619706)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2015: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2014: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 白血病幹細胞 / 急性骨髄性白血病 / がん幹細胞 / TIM-3 / galectin-9 / β-catenin / AML / LSCs

Outline of Final Research Achievements

T-cell immunoglobulin mucin-3 (TIM-3) is expressed on surface of self-renewing leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Here we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, and Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were progressively involved in transformation into myeloid leukemia from a variety of pre-leukemic disorders. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop could be therapeutic targets applicable to most types of myeloid leukemia.

Research Products

• [Journal Article] A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression. (2015)
  • Author(s): Kikushige Y, Miyamoto T, Yuda J, Jabbarzadeh-Tabrizi S, Shima T, Takayanagi S, Niiro H, Yurino A, Miyawaki K, Takenaka K, Iwasaki H, Akashi K
  • Journal Title: Cell Stem Cell. Volume: 17 Issue: 3 Pages: 341-352
  • DOI: 10.1016/j.stem.2015.07.011
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Identification of TIM-3 as a functional leukemic stem cell surface molecule in primary human myeloid leukemia (2016)
  • Author(s): 菊繁吉謙
  • Organizer: 20th Winter Meeting of the Korean Society of Blood and Marrow Transplantation
  • Place of Presentation: 韓国 ピョンチャン
  • Year and Date: 2016-02-26
  • Int'l Joint Research / Invited
• [Presentation] 白血病幹細胞抗原TIM-3の機能解明、および新規標的治療の開発 (2015)
  • Author(s): 菊繁吉謙
  • Organizer: 日本癌治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-10-29
  • Invited
• [Presentation] TIM-3 and its ligand, galectin-9 constitute a pan-myeloid autocrine loop to develop and maintain malignant stem cells in most human myeloid leukemia (2015)
  • Author(s): 菊繁吉謙
  • Organizer: 日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-18
  • Invited
• [Presentation] 白血病幹細胞におけるTIM-3/galectin-9 オートクラインシグナル機構の解明 (2015)
  • Author(s): 菊繁吉謙
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] TIM-3 and its ligand, galectin-9 constitute a pan-myeloid autocrine loop to develop and maintain malignant stem cells in most human myeloid leukemia (2014)
  • Author(s): 菊繁吉謙
  • Organizer: 米国血液学会
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2014-12-09
• [Presentation] TIM-3 and its ligand, galectin-9, constitute an autocrine loop universally critical for development of human myeloid leukemia stem cells (2014)
  • Author(s): 菊繁吉謙
  • Organizer: 分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-27
  • Invited
• [Presentation] TIM-3, a leukemia stem cell marker, plays a role in leukemic transformation through autocrine stimulatory signaling by its ligand, galectin-9 (2014)
  • Author(s): 菊繁吉謙
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-26
  • Invited