Targetable Metabolic Vulnerability in Diffuse Large B-Cell Lymphoma

Targeting metabolic alterations has become a promising therapeutic Of note, altering lipid metabolism, KDACI subsequently modulates strategy in treating hematological malignancies nowadays. Recurrent mutations of metabolic enzyme isocitrate dehydrogenase (IDH) are identified in acute myeloid leukemia and proven critically involved in leukemogenesis. AG-211, a small-molecular inhibitor of mutant IDH2, is successful in a phase I clinical trial of relapsed or refractory acutemyeloid leukemia, downregulating oncogenic metabolite 2-hydroxyglutarate and leading to differentiation of malignant myeloblasts into mature neutrophils (Stein, 2016). Besides, in natural killer/T-cell lymphoma, asparaginase-based regimens significantly improve the prognosis of the patients through targeting aspartate-related metabolites (Jaccard et al., 2011). However, metabolomic profiling and targetable metabolic vulnerability remain largely undefined in diffuse large B-cell lymphoma (DLBCL). Through unveilingmetabolic signatures, molecular subsets ofmalignancies characterized with distinct biomarkers could be identified, which opens new therapeutic opportunities, especially in the clinically and biologically heterogenous DLBCL. According to the different fingerprints of energy metabolism, DLBCL is categorized into OxPhosand non-OxPhos-subtypes. Increasedmitochondrial oxidative phosphorylation is observed in OxPhos-DLBCL, while non-OxPhos-DLBCL presents with remarkable reliance on activation of B-cell receptor signaling (Caro et al., 2012). From the view of lipid metabolism, in the journal EBioMedicine, Pera et al. (2018) report the metabolic effects of lysine deacetylase inhibitors (KDACI) panobinostat in DLBCL and uncover KDACI-induced lymphoma cell dependency on choline metabolism. This was first identified through comparison of preand posttreatment serummetabolomics patterns in patients and then confirmed by both in vitro and in vivo study that DLBCL showed an increased sensitivity to the choline pathway inhibitor after treatment with panobinostat. Their findings not only prove the power of metabolomics in identifying mechanism of action of epigenetic agents, but also reveal the potential targets for combination therapies with KDACI in DLBCL. Metabolic reprogramming is an adaption for survival during oncogenesis, disease progression, and also upon treatment, which confer for drug sensitivity.