Development of novel therapeutic strategy against chemotherapy-resistant hematological malignancies by targeting cell cycle checkpoint mechanisms

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461416
• 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: Kurosu Tetsuya 東京医科歯科大学, 医学部, 非常勤講師 (40361696)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 血液腫瘍学 / 白血病

Outline of Final Research Achievements

A dominant negative mutant of p53, p53-DD, increases Chk1-mediated G2/M checkpoint activation induced by chemotherapeutics and protects it from down regulation by inhibition of Jak2, BCR/ABL, or the PI3K/Akt pathway in hematopoietic model cell lines 32D and BaF3 or their transformants by BCR/ABL. Furthermore, the p53 activator nutlin-3 synergistically induced apoptosis with chemotherapeutics by inhibiting Chk1-mediated G2/M arrest in these cells, including cells transformed by the T315I mutant of BCR/ABL resistant to various kinase inhibitors in clinical use. Further studies suggest that p53 may inhibit the Chk1 pathway by its transcription-dependent function and through mechanisms involving the proteasomal system. The present study may shed a new light on molecular mechanisms for the therapy resistance of p53-mutated hematological malignancies and would provide valuable information for the development of novel therapeutic strategies against these diseases with dismal prognosis.

Free Research Field

血液内科学