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Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells |
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| Authors: | Tatsuya Morishima Koichi Takahashi Desmond Wai Loon Chin Yuxin Wang Kenji Tokunaga Yuichiro Arima Masao Matsuoka Toshio Suda Hitoshi Takizawa |
| Affiliation: | 1. Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan;2. Departments of Leukemia and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Contribution: Data curation, Formal analysis, Resources;3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Contribution: Data curation, Formal analysis, Methodology;4. Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China Contribution: Data curation, Methodology;5. Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Contribution: Resources;6. Laboratory of Developmental Cardiology, IRCMS, Kumamoto University, Kumamoto, Japan Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan Contribution: Data curation, Formal analysis, Methodology;7. Department of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;8. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Laboratory of Stem Cell Regulation, IRCMS, Kumamoto University, Kumamoto, Japan Contribution: Conceptualization, Writing - review & editing |
| Abstract: | 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. |
| Keywords: | acute myeloid leukemia apoptosis arachidonic acid drug repositioning phospholipid |