Development of therapeutic strategies targeting molecular mechanisms underlying the therapy resistance endowed by activated tyrosine kinase mutants in hematological malignancies

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09467
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIURA Osamu 東京医科歯科大学, 大学院医歯学総合研究科, 主任教授 (10209710)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 血液腫瘍学 / 白血病 / 分子標的療法 / チロシンキナーゼ

Outline of Final Research Achievements

Constitutively activated aberrant tyrosine kinases play important roles in development and evolution of hematopoietic malignancies and are also implicated in acquisition of therapy resistance. In the present studies we found that Pim kinases induced through the robust activation of STAT5 by FLT3-ITD protect the mTORC1/4EBP1/Mcl-1 pathway to confer the resistance to the PI3K/Akt inhibitors on FLT3-ITD-positive acute myeloid leukemia cells and, thus, represent promising therapeutic targets. We also found that, by augmenting p53-mediated downregulation of Chk1, the Mdm2 inhibitors enhances apoptosis induced in leukemic cells synergistically by chemotherapeutics and inhibitors for aberrant tyrosine kinases, which also downregulate Chk1 activation. Finally, we demonstrated that PECAM-1 enhanced CXCR4-mediated SDF-1-signaling in hematopoietic cells by binding with CXCR4 to maintain its surface expression in a similar manner with the CXCR4 mutants found in hematopoietic malignancies.

Free Research Field

血液内科学