Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with poor clinical outcomes. We have previously shown that constitutive activation of NADPH oxidase 2 (NOX2), resulting in over-production of reactive oxygen species (ROS), occurs in over 60% of AML patients. We have also shown that increased ROS production promotes increased glucose uptake and proliferation in AML cells, mediated by changes in carbohydrate metabolism. Given that carbohydrate, lipid, and protein metabolisms are all intricately interconnected, we aimed to examine the effect of cellular ROS levels on these pathways and establish further evidence that ROS rewires metabolism in AML. We carried out metabolomic profiling of AML cell lines in which NOX2-derived ROS production was inhibited and conversely in cells treated with exogenous H2O2. We report significant ROS-specific metabolic alterations in sphingolipid metabolism, fatty acid oxidation, purine metabolism, amino acid homeostasis and glycolysis. These data provide further evidence of ROS directed metabolic changes in AML and the potential for metabolic targeting as novel therapeutic arm to combat this disease.
Highlights
Reactive oxygen species (ROS) is the collective term for oxygen containing free radicals and other reactive molecules, including hydrogen peroxide (H2O2), which exert important cellular functions both in innate immunity and as cell signaling molecules [1]
Using metabolomic profiling of Acute myeloid leukemia (AML) cell lines or using a cell line incubated with glucose oxidase (GOX; an enzyme that produces H2O2), we report significant metabolic alterations in sphingolipid metabolism, fatty acid oxidation (FAO), purine metabolism, amino acid homeostasis and glycolysis
These changes in carbohydrate metabolism could be induced by the addition of GOX in an AML cell line (Mv4;11) that does not generate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) derived ROS
Summary
Reactive oxygen species (ROS) is the collective term for oxygen containing free radicals and other reactive molecules, including hydrogen peroxide (H2O2), which exert important cellular functions both in innate immunity and as cell signaling molecules [1]. Production of cellular ROS mainly occurs as a result of oxidative phosphorylation in the mitochondria, or via the transmembrane proteins, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOX) [2]. NOX2, which is expressed on the plasma membrane of hematopoietic cells, generates ROS via the univalent reduction of molecular oxygen, producing extracellular superoxide, which rapidly dismutates to H2O2, either spontaneously or via the catalytic action of the enzyme superoxide dismutase [3]. H2O2 is a relatively long lived ROS molecule which is able to traverse cell membranes, and this, alongside its ability to reversibly oxidize cysteine residues in the active sites of regulatory proteins, underlies its function as a cell signaling molecule [4]. Using hematopoietic stem progenitor cells as a model for hematopoiesis, we demonstrated that mutant N-RASG12D promotes ROS production via NADPH oxidase 2 H2O2 plays an integral role in hematopoiesis both through direct and indirect regulation of gene expression [5, 6].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
