Elucidation of TIM-3 signaling patwhay involved in leukemic stem cells

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H05340
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: Miyamoto Toshihiro 九州大学, 医学研究院, 准教授 (70343324)
• Co-Investigator(Kenkyū-buntansha): 菊繁 吉謙 九州大学, 医学研究院, 講師 (40619706) ; 赤司 浩一 九州大学, 医学研究院, 教授 (80380385)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: TIM-3 / 白血病幹細胞 / Wnt pathway

Outline of Final Research Achievements

TIM-3 is a leukemia stem cell (LSC)-specific surface molecule that is essential for maintaining the self-renewal capacity of LSCs. In the present study, we comprehensively analyzed the signaling molecules involved in the signal transduction of LSCs, and found that TIM-3 could activate canonical Wnt pathway independent of Wnt ligands via several LSCs-specific mechanisms. Furthermore, we compared TIM-3 signaling outcome between human TIM-3+ exhausted T cell and TIM-3+ LSCs, and found that LSCs, but not exhausted T cells, efficiently activate canonical Wnt pathway via the interaction between TIM-3 and galectin-9, a TIM-3 ligand. This study provides the novel evidence that TIM-3 represents a novel canonical Wnt pathway activator specifically utilized in LSCs.

Free Research Field

血液内科

Academic Significance and Societal Importance of the Research Achievements

本研究の遂行により、ヒト白血病幹細胞特異的なTIM-3シグナルの下流分子群を初めて明らかにすることができた。TIM-3シグナルはヒト白血病幹細胞の幹細胞性維持に必須のシグナルであることから、抗体によるTIM-3分子を直接標的とする治療戦略に加えて、本研究で同定した下流シグナル分子群は小分子化合物を用いたTIM-3シグナル阻害という新しい治療戦略の重要な治療標的分子候補である。したがって、ヒト白血病幹細胞を特異的に標的とする新規治療法確立するために本研究の果たした意義は非常に大きいものと考えられる。