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PRPS activity governs redox homeostasis in MYC-driven lymphoma

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE282435 | GEO | 2025/02/20

REPOSITORIES: GEO

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Project description:MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification. 32 diffuse large B-cell lymphoma samples were hybridized to HG-U133A Affymetrix GeneChips. In addition, this study contains 30 already published samples, which contribute to GSE4475 (Hummel et al. 2006 (PMID 16760442)), as well as 18 already published samples from GSE22470 (Salaverria et al. 2011 (PMID 21487109)). No re-normalisation of the published samples was performed. The complete dataset representing: (1) the 32 diffuse large B-cell lymphoma Samples, (2) the 30 Samples from GSE4475 and (3) the 18 Samples from GSE22470, is linked below as a supplementary file

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PRPS activity governs redox homeostasis in MYC-driven lymphoma

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