The adaptor protein TNF receptor-associated factor 3 (TRAF3) is a critical regulator of B lymphocyte survival. attenuated the enhanced survival of TRAF3-deficient B cells with a decrease in the pro-survival protein Mcl-1. Changes in Glut1 and Mcl-1 levels glucose uptake and B cell number in the absence of TRAF3 were all dependent upon NF-κB inducing kinase (NIK). These results indicate that TRAF3 deficiency suffices to metabolically reprogram B cells a finding that enhances our understanding of the role of TRAF3 as a tumor suppressor and suggests potential therapeutic strategies. TRAF3 is an adaptor protein with diverse context and cell-specific functions1. B cell-specific deletion of in mice (B-mutations in nearly 20% of multiple myelomas and more than 15% of diffuse large B cell lymphomas4 5 B cell survival and activation are linked to metabolic reprogramming. Chronic exposure to the pro-survival cytokine BAFF metabolically primes B cells by increasing respiratory capacity while activation through the B cell receptor (BCR) or TLR4 increases glucose metabolism6 7 IL-4- mediated enhancement of B cell survival is also dependent upon glycolysis8. B cell-specific MAP3K11 deletion of Glut1 a glucose transporter induced by activation through the BCR or TLR4 substantially reduces B cell number and inhibits antibody production6. Glut1 expression is also necessary to maintain elevated glucose metabolism and to promote survival in B cell acute lymphoblastic leukemia and multiple myeloma9 10 HXK2 is an inducible kinase that promotes glucose metabolism and cell survival and has been suggested as a therapeutic NSC 105823 target in malignancy11. HXK2 is usually upregulated in lymphocytes upon activation or cytokine activation12 13 Although TRAF3 deficiency in B cells dramatically alters survival the metabolic changes associated with this phenotype have not NSC 105823 been explored. In this study we show that TRAF3 deficiency was sufficient to induce expression of Glut1 and HXK2 in B cells. This in turn led to an increase in glucose uptake. TRAF3 deficiency resulted in metabolic reprogramming characterized by an increase in both NSC 105823 oxidative phosphorylation and anaerobic glycolysis without changes in mitochondrial mass or production of reactive oxygen species (ROS). Inhibition of glucose metabolism promoted death of TRAF3-deficient B cells. Glucose was required for long term survival of these B cells as well as maintenance of the pro-survival protein Mcl-1. In the absence of NF-κB inducing kinase (NIK) Glut1 and Mcl-1 were decreased in TRAF3-deficient B cells with associated decrease in glucose uptake. B-with positron emission tomography-computed tomography (PET-CT) older B-and mutations in human B cell malignancies4 5 The metabolic impact of loss of TRAF3 however has not been previously investigated. This study shows that B cells lacking TRAF3 undergo metabolic reprogramming characterized by increased glucose uptake and utilization. Additionally glucose availability is an important factor in their enhanced long-term survival. This suggests that in B cells enhanced glucose metabolism occurs early in oncogenesis and precedes establishment of frank malignancy. These changes are similar to metabolic B cell responses to specific receptor activation further highlighting the phenotypic similarities between lymphocyte activation and carcinogenesis28. Targeting glucose metabolism has been suggested as a potential NSC 105823 therapeutic strategy for malignancy29. Inhibition of glucose utilization may also be useful in eradicating cells with pre-malignant alterations such as TRAF3-deficient B cells to prevent lymphomagenesis. The STF-31 inhibitor of Glut1 attenuated survival of WT and TRAF3?/? B cells (Fig. 4) and B cell-specific Glut1 deletion substantially reduced B cell figures deletion of the Glut1 transporter in TRAF3-deficient B cells on their survival and oncogenic potential. Glut1 also mediates intracellular transport of oxidized vitamin C making tumor cells more susceptible to death induced by high doses of this compound31. The efficacy of therapeutic-dose vitamin C treatment in B cell malignancies in the context of TRAF3 deficiency is not yet known. The established paradigm is usually that TRAF3 inhibits B cell survival by promoting degradation of NIK kinase which in turn prospects to inhibition of non-canonical NF-κB2 activation32. B cell-specific deletion of NIK prospects to decreased mature B cell survival and and makes B cells unresponsive to BAFF activation26 33 Our.