EBV latent membrane protein 1 induces lipogenesis and confers sensitivity to inhibition of fatty acid synthase in B cells

Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein-Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro. Several B-cell malignancies are associated with latent LMP1-positive EBV infection, including Hodgkin and diffuse large B-cell lymphomas and HIV and post-transplant lymphoproliferative disorders. We have previously reported that promotion of B cell proliferation by LMP1 coincided with an induction of aerobic glycolysis. To further examine LMP1-induced metabolic reprogramming in B cells, we ectopically expressed LMP1 in an EBV-negative Burkitt lymphoma cell line preceding a targeted metabolic analysis. This analysis revealed that the most significant LMP1-induced metabolic changes were to fatty acids. In parallel, the same metabolic analysis was carried out to compare metabolic alterations in primary B cells following EBV-mediated B-cell growth transformation, which also revealed significant changes to fatty acid levels following establishment of lymphoblastoid cell lines (LCLs). Ectopic expression of LMP1 and EBV-mediated B-cell growth transformation induced fatty acid synthase (FASN) and increased lipid droplet formation. FASN is a crucial lipogenic enzyme responsible for biogenesis of fatty acids in transformed cells. Furthermore, following treatment with C75, an inhibitor of lipogenesis, we observed preferential killing of LMP1-expressing B cells. Our findings demonstrate that ectopic expression of LMP1 and EBV-mediated B-cell growth transformation leads to induction of FASN, fatty acids and lipid droplet formation, possibly pointing to a reliance on lipogenesis. Therefore, the use of lipogenesis inhibitors could potentially be used in the treatment of LMP1+ EBV associated malignancies by targeting a LMP1-specific dependency on lipogenesis.