PRPS activity governs redox homeostasis in MYC-driven lymphoma

Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. However, the temporal and epistatic relationships between the medley of pathways, factors, and mechanisms that must functionally cooperate to preserve homeostasis in Myc-overexpressing cells remain largely unknown. Here, we characterize the earliest metabolic alterations upon induction of oncogenic Myc and pinpoint the major determinants of redox balance in Myc-overexpressing lymphomas. We find that Myc rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleic acid synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. Acting at the nexus of these processes, we identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as the primary regulator of redox status in lymphoma cells. Mechanistically, Myc induces expression of the allosteric feedback refractory PRPS2 isozyme, thereby remodeling the PRPS enzyme complex to a more active state that efficiently funnels ribose-5-phosphate from the PPP to downstream nucleotides. Genetic inactivation of PRPS2 increases oxPPP flux and futile cycling, leading to increased NADPH levels and reductive stress-mediated cell death. Employing a pharmacological screen in wild-type, PRPS1- or PRPS2-knockout lymphoma cells to reveal cooperative functional interactions, we discovered that cells engineered to lack PRPS1 or PRPS2 displayed opposing differential sensitivities to compounds targeting the glutathione and thioredoxin systems, outlining effective rational combinatorial therapeutic approaches in Myc-driven lymphomas. Collectively, our work unravels how the activity of one critical node amongst the expansive metabolic architecture of a cell can be tuned by an oncogenic pathway to alter redox homeostasis and create new exploitable dependencies