Very long chain fatty acid metabolism is required in acute myeloid leukemia
Acute myeloid leukemia (AML) cells have an atypical metabolic phenotype characterized by increased mitochondrial mass as well as a greater reliance on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) for survival. To exploit this altered metabolism, we assessed publicly available databases to identify FAO enzyme overexpression. VLCAD (ACADVL) was found to be overexpressed and critical to leukemia cell mitochondrial metabolism. Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and FAO contribution to the TCA cycle, resulting in decreased viability, proliferation, clonogenic growth and AML cell engraftment. Suppression of FAO at VLCAD triggered an increase in PDH activity insufficient to increase glycolysis but resulted in ATP depletion and AML cell death with no effect in normal hematopoietic cells. Together, these results demonstrate the importance of VLCAD in AML cell biology and highlight a novel metabolic vulnerability for this devastating disease.