Abstract

Abstract TRAF3 is a signaling protein that acts as a tumor suppressor in B cells. B cell conditional TRAF3−/− mice display a remarkable expansion of B cell compartments and parenchymal B cell infiltration, attributed to enhanced B cell survival without increased proliferation. When aged, these mice develop lymphomas, and TRAF3 mutations are common in human B cell lymphoma and multiple myeloma. The mechanism of how loss of TRAF3 promotes B cell survival phenotype is not well understood; this particular role for TRAF3 is not seen in other immune cell types. We find that loss of TRAF3 leads to increased uptake of glucose in B cells in vitro and in vivo. This is accompanied by increased oxidative phosphorylation and glycolysis. In the absence of TRAF3, expression of Glut1 and Hexokinase II, two molecules important for glucose metabolism, is increased. Treatment of B cells with Glut1 inhibitor or the competitive glycolysis inhibitor 2-DG attenuates cell survival, and B cell viability is also substantially reduced in a glucose-free environment. Mechanistically, loss of TRAF3 leads to the induction of Pim2 kinase. Pim2 in turn promotes the protein stability of the oncogenic transcription factor c-Myc, known to drive expression of glycolytic genes. Our study shows that B cell deficiency of TRAF3 is sufficient for altered metabolic programming, consistent with a premalignant abnormal survival phenotype.

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