Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells

• Published in: Cancer science Vol. 115; no. 1; pp. 197 - 210
• Main Authors: Morishima, Tatsuya, Takahashi, Koichi, Chin, Desmond Wai Loon, Wang, Yuxin, Tokunaga, Kenji, Arima, Yuichiro, Matsuoka, Masao, Suda, Toshio, Takizawa, Hitoshi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-01-2024; John Wiley and Sons Inc
• Subjects: Acute myeloid leukemia; Adaptation; Anti-inflammatory agents; Apoptosis; Arachidonic acid; Cancer therapies; Cell culture; Clinical trials; Cloning; Colorectal cancer; Cytokines; Drug delivery; Drug metabolism; drug repositioning; Enzymatic activity; Enzymes; Genes; IDH2 gene; Inflammation; Intracellular; Isocitrate dehydrogenase; Leukemia; Medical prognosis; Metabolism; Metabolites; Mutants; Mutation; Original; Patients; phospholipid; Phospholipids; Phosphorylation; arachidonic acid; apoptosis; acute myeloid leukemia; drug repositioning; phospholipid
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.15994

Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid‐mediated apoptosis. The release of this metabolic adaptation by FDA‐approved anti‐inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.
Phospholipid metabolic adaptation in IDH2 mutant acute myeloid leukemia (AML) cells underlies their resistance to apoptosis. Food and Drug Administration‐approved anti‐inflammatory drugs targeting the metabolism of arachidonic acid can sensitize IDH2 mutant AML cells to apoptosis.