Microenvironment-Mediated Bim Down-Regulation through Induction of Microrna-181a Protects Cells From Apoptosis In Mantle-Cell and Other Non-Hodgkin B-Cell Lymphomas

Abstract 3118

Follicular dendritic cells (FDCs), essential components of the lymph node microenvironment, regulate and support B lymphocyte differentiation, survival, and lymphoma progression. Here, we demonstrated that adhesion of mantle cell and other non-Hodgkin lymphoma cells to FDCs reduced cell apoptosis, associated with decreased levels of Bim, a pro-apoptotic protein. Bim down-regulation was epigenetically regulated via up-regulation of microRNA-181a (miR-181a). miR-181a overexpression decreased, whereas miR-181a inhibition increased Bim levels by directly targeting Bim. Furthermore, we found that cell adhesion-up-regulated miR-181a contributes to FDC-mediated cell survival through Bim down-regulation, implicating miR-181a as an upstream effector of the Bim-apoptosis signaling pathway. miR-181a inhibition and Bim up-regulation significantly suppressed FDC-mediated protection against apoptosis in lymphoma cell lines and primary lymphoma cells. Thus, FDCs protect B-cell lymphoma cells against apoptosis, in part through activation of a miR-181a-dependent mechanism involving down-regulation of Bim expression. We demonstrate, for the first time, that cell-cell contact controls tumor cell survival and apoptosis via microRNA in mantle cell and other non-Hodgkin lymphomas. Regulation of microRNAs by B-cell-FDC interaction may support B-cell survival, representing a novel molecular mechanism for cell-adhesion mediated drug resistance (CAM-DR) and a potential therapeutic target in B-cell lymphomas.