Elucidation of the function of exhaustion-related molecules in human leukemic stem cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H06250
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: Kikushige Yoshikane 九州大学, 医学研究院, 助教 (40619706)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: TIM-3 / 白血病幹細胞

Outline of Final Research Achievements

In the present study, we tried to clarify the function of TIM-3 signaling in human acute myeloid leukemia stem cells. TIM-3 has been originally identified as a T-cell exhaustion marker; however, its function and signaling in leukemic stem cells are still elusive. We identified that galectin-9, a ligand for TIM-3, ligation to TIM-3 recruits HCK to its cytoplasmic tail and HCK is subsequently activated in leukemic stem cells, leading to the activation of canonical Wnt pathway through the interaction with p-120 catenin even in the absence of Wnt ligands. TIM-3 signaling directly activates the canonical Wnt pathway and induces the aberrant beta-catenin accumulation independent of conventional Wnt ligands. Thus, TIM-3 signaling is a novel and specific canonical Wnt pathway regulator in human leukemic stem cells.

Free Research Field

血液内科

Academic Significance and Societal Importance of the Research Achievements

Canonical Wnt pathway関連遺伝子変異によるβカテニン活性化機構が多くの固形腫瘍では知られている一方で、ヒト急性骨髄性白血病においてはそのような遺伝子変異が認められないことから全く異なるメカニズムでβカテニン活性化が生じていると考えられてきたが詳細は不明であった。本研究により、白血病幹細胞特異的分子であるTIM-3シグナルとその下流の分子群がCanonical Wnt pathwayを直接活性化する新しい分子機構であることを見出した。すなわち、ヒト急性骨髄性白血病における遺伝子変異非依存的βカテニン活性化機構としてTIM-3シグナルとその下流分子群の同定に至った。