Abstract
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 cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating Myc-driven lymphomas.
Overview
- bullet: The study aims to elucidate the temporal and functional relationships between various pathways, factors, and mechanisms that control redox homeostasis in Myc-overexpressing B cell lymphomas.
- bullet: The study focuses on the role of Myc in regulating redox homeostasis, particularly through the hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme.
- bullet: The study proposes a therapeutic approach targeting PRPS1 or PRPS2 to treat Myc-driven lymphomas, which shows opposite sensitivity or resistance to chemotherapeutic agents affecting the thioredoxin and glutathione network.
Comparative Analysis & Findings
- bullet: The study found that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, leading to a more oxidative state of the cells.
- bullet: The study identified Myc-dependent hyperactivation of the PRPS enzyme as a primary regulator of redox status in lymphoma cells.
- bullet: Genetic inactivation of the PRPS2 isozyme led to elevated NADPH levels and reductive stress-mediated death in Myc-driven lymphoma cells, whereas inactivation of PRPS1 had no significant effect.
Implications and Future Directions
- bullet: The study provides a therapeutic blueprint for treating Myc-driven lymphomas by targeting PRPS1 or PRPS2, which could elicit opposing sensitivity or resistance to chemotherapeutic agents.
- bullet: Further studies are needed to investigate the mechanisms by which PRPS1 and PRPS2 regulate redox status and how they interact with the thioredoxin and glutathione network.
- bullet: The study's findings could be expanded to other tumor types and/or conditions characterized by Myc overexpression or altered redox homeostasis.