A fundamental requirement for growth of rapidly proliferating cells is metabolic adaptation to promote synthesis of biomass1. ACLY is a critical enzyme responsible for synthesis of cytosolic acetyl-CoA and de novo fatty acid synthesis and links vital pathways such as carbohydrate and lipid metabolism2. The functional significance of phosphorylation of ACLY on tyrosine residue is not well understood. Here we show using mass spectrometry-driven phosphoproteomics that ACLY is phosphorylated and functionally regulated at an evolutionary conserved residue, Y682 in ALK+ lymphoma. Physiologic signals such as epidermal growth factor stimulation in epithelial cells and T-cell receptor activation in primary human T-cells result in rapid phosphorylation of ACLY at Y682.In vitro kinase assays demonstrate that Y682 is directly phosphorylated by multiple tyrosine kinases, including ALK, ROS1 and LTK. Oncogenically activating structural alterations such as gene fusions, amplification or point mutations of ALK tyrosine kinase result in constitutive phosphorylation of ACLY in diverse forms of primary human cancer such as lung cancer, ALCL and neuroblastoma. Expression of a phosphorylation-defective ACLY-Y682F mutant in NPM-ALK+ ALCL decreases ACLY activity and attenuates lipid synthesis. Metabolomic analyses reveal that ACLY-Y682F expression results in increased β-oxidation of 13C-oleic acid-labeled fatty acid with increased labeling of +2-citrate and +18-oleyol carnitine and oxygen consumption rate (OCR).Expression of ACLY-Y682F dramatically decreases cell proliferation, impairs clonogenicity and abrogates tumor growth in vivo. Our results reveal a novel mechanism for direct ACLY regulation that is subverted by NPM-ALK.These findings have significant implications for novel therapies targeting ACLY in other tyrosine kinase mediated cancers.