PRPS activity tunes redox homeostasis in Myc-driven lymphoma

Area of Science:

• Oncology
• Cellular Metabolism
• Biochemistry

Background:

• Myc hyperactivation is a key driver of lymphomagenesis, coordinating metabolic reprogramming.
• Redox homeostasis is critical for cancer cell survival and proliferation.
• Understanding the interplay between Myc, metabolism, and redox balance is crucial for therapeutic development.

Purpose of the Study:

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

Main Methods:

• Analysis of metabolic pathways (oxidative pentose phosphate pathway, nucleotide synthesis, mitochondrial respiration) in Myc-overexpressing lymphoma cells.
• Genetic inactivation of PRPS1 and PRPS2 isozymes.
• Pharmacological screening of chemotherapeutic agents targeting the thioredoxin and glutathione network.

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 phosphoribosyl pyrophosphate synthetase (PRPS) is a primary regulator of redox status.
• Genetic inactivation of PRPS2, but not PRPS1, causes reductive stress-mediated death due to elevated NADPH levels.
• Targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance to specific chemotherapeutic agents.

Conclusions:

• Myc-driven lymphoma pathogenesis involves intricate metabolic and redox regulation.
• PRPS enzymes are critical regulators of redox homeostasis and potential therapeutic targets in lymphoma.
• Targeting PRPS1 or PRPS2 offers a potential therapeutic blueprint for Myc-driven lymphomas, with distinct implications for chemotherapy sensitivity.