PRPS activity tunes redox homeostasis in Myc-driven lymphoma

Area of Science:

• Oncology
• Cellular Metabolism
• Biochemistry

Background:

• Myc hyperactivation drives lymphomagenesis by altering cellular metabolism.
• Redox homeostasis is critical for maintaining cellular equilibrium in cancer.
• Understanding the interplay between Myc and redox pathways is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate the temporal and functional relationships between pathways controlling redox homeostasis in Myc-overexpressing B cell lymphomas.
• To identify key regulators of redox status in lymphoma cells.
• To explore therapeutic strategies targeting these regulators.

Main Methods:

• Investigated metabolic pathways (oxPPP, nucleotide synthesis, mitochondrial respiration) in Myc-overexpressing B cells.
• Assessed the role of phosphoribosyl pyrophosphate synthetase (PRPS) enzyme in regulating redox status.
• Utilized genetic inactivation of PRPS1 and PRPS2 isozymes.
• Conducted a pharmacological screen to evaluate drug sensitivity.

Main Results:

• Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, leading to an oxidative state.
• Myc-dependent hyperactivation of PRPS is a primary regulator of redox status.
• Genetic inactivation of PRPS2, but not PRPS1, in MYC-driven lymphoma cells causes elevated NADPH and reductive stress-mediated death.
• Targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance to chemotherapeutic agents.

Conclusions:

• Myc-driven lymphoma pathogenesis involves significant alterations in cellular metabolism and redox homeostasis.
• PRPS enzymes are key regulators of redox balance in MYC-driven lymphomas.
• Targeting PRPS1 or PRPS2 presents a potential therapeutic blueprint for treating MYC-driven lymphomas by modulating redox status and drug sensitivity.