Elucidation of leukemia clone survival mechanism via lipid metabolic adaptation

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08397
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kumamoto University
• Principal Investigator: Morishima Tatsuya 熊本大学, 国際先端医学研究機構, 特任講師 (40421375)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 急性骨髄性白血病 / IDH遺伝子変異 / 薬剤耐性 / 脂肪酸代謝 / ドラッグ・リポジショニング / 抗炎症薬

Outline of Final Research Achievements

Although cell survival/proliferation mechanism via lipid metabolic adaptation in leukemia cells with isocitrate dehydrogenase (IDH) mutation has been suggested, the precise molecular mechanism remained unclear. In this study, we identified that phospholipase C (PLC) gene expression was downregulated by methylation of PLC gene promoter regions, which downregulated intracellular arachidonic acid level and resulted in resistance to apoptosis in IDH2 mutant cells. To overcome this apoptosis resistance, we revealed that specific inhibitors of arachidonic acid metabolism in combination with specific inhibitor of mutant IDH2 could induce apoptosis in IDH2 mutant leukemia cells.

Free Research Field

血液学

Academic Significance and Societal Importance of the Research Achievements

本研究により脂肪酸代謝適応による生存・増殖機構というIDH2変異白血病における新たな病態生理が明らかとなり、これに対し抗炎症薬として使われるアラキドン酸代謝酵素COX-2/5-LOXの阻害剤を変異型IDH2特異的阻害剤と併用することでIDH2変異白血病に細胞死を誘導できることが明らかとなった。これにより従来の変異型IDH2阻害剤に耐性を示す症例について抗炎症薬を併用することにより予後を改善できる可能性が示された。