Metabolic heterogeneity in molecular subtypes of Diffuse Large B-Cell Lymphomas

B-cell receptor (BCR) survival signals are central to pathogenesis of certain Diffuse Large B-Cell Lymphomas (DLBCLs). Among transcriptionally-defined groups of DLBCL, the “OxPhos” subset displays increased expression of genes involved in mitochondrial oxidative phosphorylation but lacks an intact BCR signaling network, suggesting dependence on alternative survival mechanisms. We have conducted an integrative analysis using proteomics, mitochondrial respirometry and metabolomics that has unraveled previously unappreciated metabolic distinctions and subtype-specific quantitative differences in the DLBCL metabolome. We show that compared with BCR-dependent DLBCLs, nutrient and energy metabolism in OxPhos-DLBCL have a significant mitochondrial component marked by elevated mitochondrial electron transport chain (ETC) activity, increased mitochondrial ATP production, greater incorporation of fatty acid- and glucose-derived carbons into the TCA cycle, and increased lipogenesis from these carbon substrates. In comparison, the “non-OxPhos” DLBCLs have greater glycolytic flux typical of the Warburg phenotype. These findings provide a clear example of heterogeneity in fuel utilization pathways even within the same disease entity. Importantly, the distinct metabolic fingerprints we have identified are associated with survival mechanisms and predictable metabolic vulnerabilities that segregate with the presence/absence of functional BCR signaling. We show mitochondrial fatty acid oxidation and glutathione synthesis are distinct metabolic features of OxPhos-DLBCLs selectively required for their survival. Metabolic signatures may provide important insights into the molecular heterogeneity of DLBCL and reveal rational targets in these lymphomas.