Advances in Understanding of Metabolism of B-Cell Lymphoma: Implications for Therapy

Abstract

There have been significant recent advances in the understanding of the role of metabolism in normal and malignant B-cell biology. Previous research has focused on the role of MYC and mammalian target of rapamycin (mTOR) and how these interact with B-cell receptor signaling and hypoxia to regulate glycolysis, glutaminolysis, oxidative phosphorylation (OXPHOS) and related metabolic pathways in germinal centers. Many of the commonest forms of lymphoma arise from germinal center B-cells, reflecting the physiological attenuation of normal DNA damage checkpoints to facilitate somatic hypermutation of the immunoglobulin genes. As a result, these lymphomas can inherit the metabolic state of their cell-of-origin. There is increasing interest in the potential of targeting metabolic pathways for anti-cancer therapy. Some metabolic inhibitors such as methotrexate have been used to treat lymphoma for decades, with several new agents being recently licensed such as inhibitors of phosphoinositide-3-kinase. Several other inhibitors are in development including those blocking mTOR, glutaminase, OXPHOS and monocarboxylate transporters. In addition, recent work has highlighted the importance of the interaction between diet and cancer, with particular focus on dietary modifications that restrict carbohydrates and specific amino acids. This article will review the current state of this field and discuss future developments.

Keywords: B-cell metabolism; germinal center biology; glutaminase; lymphoma metabolism; mammalian target of rapamycin; monocarboxylate transporters; oxidative phosphorylation; phosphatidylinositide-3-kinase.

Figure 1

Metabolic pathways in B-cell lymphoma. Imported glucose (GLC) is metabolized via glycolysis with multiple branching pathways utilizing glycolytic intermediates and pyruvate (PYR): glucose-6-phosphate (G6P) can be metabolized via the pentose phosphate pathway (PPP) to ribose-5-phosphate (R5P); 3-phosphoglycerate (3PG) can be used for serine (SER) and glycine (not shown) synthesis and contribute to one-carbon (1C) metabolism and the synthesis of purines and pyrimidines; glycolytic pyruvate can be converted to lactate (LAC) (while regenerating NAD⁺) and exported out of the cell or metabolized further in mitochondria and enter the tricarboxylic acid (TCA) cycle as acetyl coenzyme A (AcCoA). Glutamine (GLUT) conversion to glutamate (GLU) is one of anaplerotic pathways that can feed the TCA cycle. These metabolic pathways are regulated at multiple levels and via several modes such as kinase signaling triggered by BCR activation (shown in orange) and transcription factor MYC (shown as yellow clouds). Other abbreviations used in the figure: Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), glycogen synthase kinase 3 (GSK3), mammalian target of rapamycin complex 1 (mTORC1), hexokinase (HK), phosphoglycerate dehydrogenase (PHGDH), serine hydroxymethyl transferase 1/2 (SHMT1/2), dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), monocarboxylate transporter 1/4 (MCT1/4), lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), glutaminase 1 (GLS1), oxoglutarate dehydrogenase (OGDH), individual complexes comprising oxidative phosphorylation (CI-V; shown in green).

Figure 2

Metabolic inhibitors and their targets in B-cell lymphoma. Pro-proliferative kinase signaling downstream of the BCR can be targeted by inhibiting BTK (e.g., ibrutinib or acalabrutinib), PI3K (e.g., idelalisib, copanlisib, duvelisib, umbralisib) and mTORC1 (e.g., temsirolimus). Enzymes involved in glucose and 1C metabolism can be inhibited at the point of serine synthesis via PHGDH (e.g., PH-755) and tetrahydrofolate regeneration by dihydrofolate reductase (methotrexate) and thymidylate synthesis by thymidylate synthase (e.g., methotrexate). Lactate efflux can be blocked by inhibition of MCT1 by AZD3965. Mitochondrial carbon metabolism can be targeted via inhibition of glutaminase (e.g., telaglenastat) and by inhibiting lipoate dependent enzymes pyruvate dehydrogenase and oxoglutarate dehydrogenase (e.g., devimistat). Mitochondrial oxidative phosphorylation and NADH oxidation can be targeted by specific inhibition of respiratory complex I (e.g., IM156, metformin, IACS-010759).