biostudies-literatureMacMillan ACNational Institutes of Health National Cancer InstituteBLRD VANIEHS NIH HHSNCI NIH HHSNational Institutes of HealthNIGMS NIH HHSUS Department of Veterans Affairs103649https://www.ebi.ac.uk/biostudies/studies/S-EPMC12166406biostudies-literatureUnknown84Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma ceRedox biologyPRPS activity tunes redox homeostasis in Myc-driven lymphoma.PMC121664062I01BX001110R25CA261610R35 GM133561R01CA2309045T32ES007250-34I01 BX001110R01CA287260R01 CA230904R25 CA261610R35GM133561R01 CA287260T32 ES007250Zumwalde SYang JCunningham JTMeller JCzyzyk-Krzeska MFGertz KRMacMillan ACKarki BPatel JGfalsePRPS activity tunes redox homeostasis in Myc-driven lymphoma.Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in Myc-driven lymphoma ce2025-01-01T00:00:00Z2025 Jul2026-06-03T03:05:08.107Z2026-04-23T03:13:25.039ZS-EPMC121664064044664210.1016/j.redox.2025.103649