Analysis of the interaction effect of PECAM-1 and bone marrow stromal cells on leukemia cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17371
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Umezawa Yoshihiro 東京医科歯科大学, 東京医科歯科大学病院, 助教 (50813218)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: PECAM-1 / CLL / leukemia / bone marrow stromal cell / SHP2

Outline of Final Research Achievements

Pharmacological analyses using inhibitors suggested that PECAM-1 may activate the PI3K/Akt/mTORC pathway through SHP2 regulation. PECAM-1 over-expressed 32Dcl3 cells demonstrated no advantage on cell proliferation or survival in a co-culture system with bone marrow stromal cells compared to control cells. However, chronic lymphocyte leukemia(CLL) cells expressing PECAM-1 showed significant advantage on its survival when co-cultured with bone marrow stromal cells, and the effect was enhanced with over-expression of PECAM-1 on bone marrow stromal cells. Interestingly, this favoring effect of PECAM-1 expression on CLL cell survival was diminished by using BTK inhibitor.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

CLLにおいて細胞表面のPECAM-1を通じた骨髄間質細胞とのinteractionが細胞生存に対し有利な環境を付与していることが示唆され、BTK阻害薬によりその効果は抑制された。PECAM-1はBTKなどによりそのimmunotyrosine-based inhibitory motif(ITIM)のチロシンがリン酸化され、SHP2などをリクルートすることでシグナル伝達を行い、骨髄微小環境を介した治療抵抗性に寄与している可能性が考えられ、また、BTK阻害薬はこのような骨髄微小環境とCLLの相互作用も包括的に治療標的としうることが示唆される。