Targeting minimal residual leukemic stem cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02951
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kanazawa University
• Principal Investigator: Miyamoto Toshihiro 金沢大学, 医学系, 教授 (70343324)
• Co-Investigator(Kenkyū-buntansha): 菊繁 吉謙 九州大学, 大学病院, 講師 (40619706)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 急性白血病 / 白血病幹細胞 / 微小残存病変 / 治療抵抗性 / TIM-3

Outline of Final Research Achievements

Relapse still remains the crucial obstacle for the treatment of AML. We evaluated measurable residual leukemic stem cells (MR-LSC) by utilizing TIM-3 expression, a functional marker of LSC. Gene analysis of CD34+CD38- cells disclosed TIM-3+ cells share patient-specific mutations identical to the initial, remission, and relapsed AML clones, but TIM-3- did not. RNA-seq analysis demonstrated most CD34+ cells at diagnosis/relapse belonged to the same AML-cluster, showing higher LSC-related expression. Notably a tiny population at remission was again distributed within the same AML-cluster. TIM-3 was highly expressed in AML-cluster at diagnosis/relapse as well as remission. Frequency of CD34+CD38-TIM-3+ LSC were enumerated by flowcytometry in patients with remission. Only ~20% who achieved MR-LSClow status relapsed, but ~80% with MR-LSCint/high relapsed. MR-LSC is useful to predict outcomes of AML, and targeting TIM-3 signaling would pave the way for eradicating self-renewing AML-LSC.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

LSCはAML治療抵抗性獲得の中心的な役割を担うが、治療後に微小残存するLSCのみを純化して直接研究対象として残存潜伏する機構を解析することは技術的に困難であった。我々が同定したLSC機能分子TIM-3を指標とすることで全治療期を通して真の治療抵抗へと進展する微小残存LSCを正確に捕捉することが可能となり、LSCが依存する生存機構をシングルセル・マルチオミクス解析で明らかにした。さらにTIM-3シグナルによるLSCの制御機構を解明したことで、CD34+CD38-TIM-3+ LSCを直接標的とした治療開発を行なっている。