Identification of novel therapeutic targets against refractory AML using genome editing

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K10111
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Shimane University
• Principal Investigator: Fukuda Seiji 島根大学, 学術研究院医学・看護学系, 教授 (30273147)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 急性骨髄性白血病 / 薬剤耐性

Outline of Final Research Achievements

This study was to determine the molecular mechanism responsible for the refractory FLT3 mutated acute myeloid leukemia. Using the mRNA microarray screening, we identified a transcriptional factor Runx1 as a candidate molecule responsible for the resistance of the FLT3 mutated acute myeloid leukemia. Our subsequent analyses validate that Runx1 is indeed involved and modulate resistance regulated by chemokine Cxcl12 in FLT3 mutated acute myeloid leukemia cells. We identified that changes in expression level in FLT3 mutated acute myeloid leukemia cells, which was dependent on the magnitude of Cxcl12/Cxcr4 signaling, regulates resistance of FLT3 mutated acute myeloid leukemia against FLT3 inhibitors. This study suggest that Runx1 represents potential target for the treatment of FLT3 mutated acute myeloid leukemia that are refractory against FLT3 inhibitors.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

急性骨髄性白血病の予後は芳しくない。特にFLT3変異陽性のケースは予後が悪い。近年、FLT3変異に対する抑制剤(FLT3抑制剤）が承認され使用されているが、大部分は治療抵抗性となる。治療抵抗性の分子メカニズムは様々なものが知られているが、この研究ではFLT3抑制剤の治療抵抗性のメカニズムを新たに見出した。すなわち、治療抵抗性を克服しうる新たな治療標的が同定できた。この研究をさらに発展させることでFLT3抑制剤の治療効果が改善し、患者の予後改善に結びつく可能性がある点で意義のある研究である。