Diffuse Large B-Cell Lymphomas Are Metabolically Heterogeneous

Diffuse large B-cell lymphomas (DLBCL) are aggressive tumors with genetic and clinical variability. DLBCL has been classified into several molecular subgroups based on transcriptional profiling, suggesting that different pathogenic mechanisms and therapeutic targets may exist within this disease. For example, B-cell receptor (BCR) signaling is critical to the survival of a subset of DLBCLs, and inhibitors of BCR signaling show activity in these tumors. Another DLBCL subgroup shows upregulation of genes involved in mitochondrial oxidative phosphorylation (OxPhos), but the functional implications of this transcriptional signature are unclear. OxPhos DLBCLs do not have functional BCR signaling and are insensitive to BCR inhibition, suggesting that they are dependent on alternative survival mechanisms. Caro and colleagues hypothesized that the OxPhos subgroup is metabolically distinct from other DLBCLs and showed that the mitochondrial proteome of OxPhos DLBCL cells was significantly enriched for enzymes involved in mitochondrial β-oxidation, the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation, and detoxification of reactive oxygen species compared with non-OxPhos DLBCL cells. Furthermore, OxPhos DLBCL cells utilized nutrients differently than non-OxPhos DLBCL cells, as OxPhos cells diverted glucose into the TCA cycle and generated ATP and biosynthetic intermediates from fatty acid oxidation. Most of the total cellular energy of OxPhos cells was derived from mitochondrial oxidative metabolism as opposed to BCR DLBCL, which primarily depended on aerobic glycolysis. Notably, OxPhos DLBCL cells were selectively sensitive to pharmacologic or genetic inhibition of fatty acid oxidation, suggesting that the metabolic features of this sub-type could be exploited therapeutically. These findings indicate that a unique metabolic program is activated in a subset of DLBCLs that confers growth and survival advantages and highlight the metabolic heterogeneity that can exist even within a single tumor type.

Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphomas. Cancer Cell 2012;22:547–60.

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