Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma

Abstract

SUMMARY Molecular signatures have identified several subsets of Diffuse Large B-Cell Lymphoma (DLBCL) and rational targets within the B-cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling, but is functionally undefined. We show that compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the TCA cycle and increased glutathione levels. Importantly, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.

Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

“…The OCI-Ly7 cell line, the in vitro model bearing the 11q24.3 gain, is usually considered of GCB origin but is more likely representative of a type of DLBCL intermediate between GCB and ABC DLBCL. 35 Indeed, also in our hands, the cell line expressed markers typical of both GCB (BCL6, PAX5) and non-GCB DLBCL (IRF4, PRDM1, XBP1) (data not shown). These observations suggest that the lesion might be relevant in a subgroup of DLBCL derived from the non-GC phase in accordance with the observed higher ETS1 RNA levels in ABC than in GCB DLBCL.…”

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

“…Recent studies have shown that utilization of alternative carbon sources affects tumor evolution, and the role of oxidative phosphorylation in cancer metabolism has not been fully appreciated (46,(51)(52)(53)(54). Furthermore, the ability of normal as well as cancer cells to rapidly adjust their metabolic behavior in response to environmental conditions and cellular requirements is essential to survival and the metabolic requirements of proliferating and nonproliferating cells are distinct, as are the metabolic demands underlying tumor initiation, metastasis, and growth at distant sites (55,56).…”

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

“…For example, CCC-defined BCR-DLBCLs include BCR-dependent tumors of both ABC and GCB COO subtypes, 16,17 whereas CC-classified OxPhos-DLBCLs include BCRindependent tumors. 7,16 Our previous functional analyses of DLBCL subtypes also uncovered quantitative proteome-and metabolome-level signatures associated with differences in nutrient and energy metabolism. 7 Specifically, these studies showed that BCR-dependent DLBCLs have greater glycolytic flux typical of the Warburg phenotype.…”

“…For example, CCC-defined BCR-DLBCLs include BCR-dependent tumors of both ABC and GCB COO subtypes, 16,17 whereas CC-classified OxPhos-DLBCLs include BCRindependent tumors. 7,16 Our previous functional analyses of DLBCL subtypes also uncovered quantitative proteome-and …”

“…[3][4][5] Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. [7][8][9][10][11][12] Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'.…”