Abstract
Background: In Acute Myeloid Leukemia (AML), a complete response to chemotherapy is usually obtained after conventional chemotherapy but overall patient survival is poor due to highly frequent relapses. As opposed to chronic myeloid leukemia, B lymphoma or multiple myeloma, AML is one of the rare malignant hemopathies the therapy of which has not significantly improved during the past 30 years despite intense research efforts. One promising approach is to determine metabolic dependencies in AML cells. Moreover, two key metabolic enzymes, isocitrate dehydrogenases (IDH1/2), are mutated in more than 15% of AML patient, reinforcing the interest in studying metabolic reprogramming, in particular in this subgroup of patients. Methods: Using a multi-omics approach combining proteomics, lipidomics, and isotopic profiling of [U-13C] glucose and [U-13C] glutamine cultures with more classical biochemical analyses, we studied the impact of the IDH1 R132H mutation in AML cells on lipid biosynthesis. Results: Global proteomic and lipidomic approaches showed a dysregulation of lipid metabolism, especially an increase of phosphatidylinositol, sphingolipids (especially few species of ceramide, sphingosine, and sphinganine), free cholesterol and monounsaturated fatty acids in IDH1 mutant cells. Isotopic profiling of fatty acids revealed that higher lipid anabolism in IDH1 mutant cells corroborated with an increase in lipogenesis fluxes. Conclusions: This integrative approach was efficient to gain insight into metabolism and dynamics of lipid species in leukemic cells. Therefore, we have determined that lipid anabolism is strongly reprogrammed in IDH1 mutant AML cells with a crucial dysregulation of fatty acid metabolism and fluxes, both being mediated by 2-HG (2-Hydroxyglutarate) production.
Highlights
Cancer cells, including acute myeloid leukemia (AML) cells, grow and divide faster and more efficiently than normal cells, which increase their demand for energy, biosynthetic precursors, and macromolecular synthesis [1,2,3,4]
Changes in cell metabolism represent a key hallmark in cancer biology [3] and it has been largely demonstrated that metabolic reprogramming in cancer cells occurs far beyond the Warburg Effect [7,8]
Dysregulation of lipid-associated pathways is increasingly described in tumors [9,10,11,12], and different studies have demonstrated that lipogenesis is significantly up-regulated in human cancers, in particular to respond to higher demands for membrane biogenesis [13,14,15] or to serve as energy source when nutrients are limited [16,17]
Summary
Cancer cells, including acute myeloid leukemia (AML) cells, grow and divide faster and more efficiently than normal cells, which increase their demand for energy, biosynthetic precursors, and macromolecular synthesis [1,2,3,4]. Methods: Using a multi-omics approach combining proteomics, lipidomics, and isotopic profiling of [U-13C] glucose and [U-13C] glutamine cultures with more classical biochemical analyses, we studied the impact of the IDH1 R132H mutation in AML cells on lipid biosynthesis. Isotopic profiling of fatty acids revealed that higher lipid anabolism in IDH1 mutant cells corroborated with an increase in lipogenesis fluxes. We have determined that lipid anabolism is strongly reprogrammed in IDH1 mutant AML cells with a crucial dysregulation of fatty acid metabolism and fluxes, both being mediated by 2-HG (2-Hydroxyglutarate) production
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