Epstein-Barr virus latent membrane protein-1 protects B-cell lymphoma from rituximab-induced apoptosis through miR-155-mediated Akt activation and up-regulation of Mcl-1.

Rituximab is a CD20-targeted monoclonal antibody widely used in the treatment of B-cell lymphoma. Previously, we have shown that Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) increases chemoresistance in malignant cancer cells. In this study we examined the effects of LMP1 on the response of B-cell lymphoma cell lines to rituximab. Here we show for the first time that LMP1 activates the Akt pathway and up-regulates Mcl-1 through miR-155 expression, which contributes to the survival of rituximab-treated B-cell lymphoma cells. Furthermore, Akt inhibition or knockdown of Mcl-1 and miR-155 was found to be an efficient strategy to overcome rituximab resistance caused by LMP1 expression. Thus, we propose Akt and Mcl-1 and miR-155 as molecular targets for therapeutic intervention in the treatment of EBV-associated B-cell lymphoma with rituximab.