Development of combined molecular target therapy against hematopoietic malignancies expressing constitutively activated tyrosine kinases

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591384
• 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, 医歯(薬)学総合研究科, 教授 (10209710)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 急性骨髄性白血病 / 骨髄増殖性腫瘍 / チロシンキナーゼ阻害薬 / 分子標的療法 / FLT3 / Jak2 / STAT5 / PECAM-1

Outline of Final Research Achievements

The molecular mechanisms for resistance of acute myeloid leukemia and myeloproliferative neoplasms, such as chronic myeloid leukemia, against chemotherapy and molecular target therapy conferred by constitutively activated tyrosine kinases, such as FLT3-ITD, BCR/ABL and Jak2-V617 were analyzed. These aberrant tyrosine kinases were found to enhance Chk1-mediated cell cycle checkpoint mechanisms induced by chemotherapeutics to confer resistance to chemotherapy or protect the downstream mTOR pathway from inhibition of the PI3K/Akt pathway by robustly activating STAT5 to confer resistance to the PI3K/Akt inhibitors. Combined therapeutic strategies to control these resistance mechanisms have shown to induce apoptosis of leukemic cells synergistically and very effectively.

Free Research Field

血液内科学