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

SIMPLE SUMMARY: The role of metabolism in normal and malignant B-cell biology is an area of rapid evolution and interest. While previous research has focused on glycolysis, glutaminolysis and oxidative phosphorylation, recent advances have demonstrated the importance of additional metabolic pathways and how these interact with oncogenic drivers and cellular signaling. This article reviews the current understanding of normal germinal center metabolism and how this relates to the metabolism of germinal center-derived lymphomas. There is increasing interest in the potential of targeting metabolic pathways for anti-cancer therapy, with some new agents already entering clinical trials. This article will also review novel enzymatic targets and pathways, and how existing agents modulate metabolism. 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.