Disruption of folliculin interacting protein-1 inhibits Myc-driven glycolysis and sensitizes B cells to apoptosis following activation and chemotherapy.

Abstract Folliculin interacting protein-1 (Fnip1) is a cytoplasmic protein originally discovered through its interaction with Folliculin (Flcn), a tumor suppressor mutated in the hamartoma disorder Birt-Hogg Dubé syndrome. Fnip1 and Flcn both interact with the master metabolic regulator AMPK. Our previous studies have shown that Fnip1 is required for the development of B-cells past the late pre-B stage. Fnip1 deficiency also prevented the development of pre-B cell lymphoma in Eµ-Myc transgenic mice. In this study, we examined the potential efficacy of Fnip1 inhibition in cancer and autoimmunity treatments by disrupting Fnip1 expression in B lymphoma cells and activated IgM-expressing B cells. We show that siRNA-mediated depletion of endogenous FNIP1 from a human B cell line expressing a conditional Myc allele increases oxidative phosphorylation in a glutamine-dependent manner and decreases Myc-induced glycolysis, which supports cell division (Warburg Effect). Disruption of Fnip1 also reduces Myc-induced glycolysis and increases apoptosis of murine pre-B Eµ-Myc cells in response to nutrient deprivation and chemotherapeutic drugs ex vivo. Fnip1 deficient B cells expressing an IgMHEL transgene exhibit a “tolerant” phenotype and exhibit increased sensitivity to apoptosis following BCR crosslinking. These results suggest that inhibition of Fnip1 may provide a novel strategy to sensitize lymphoma cells to apoptosis, and/or tolerize or delete activated B cells in autoimmune diseases.