Targeting Mir-548m-HDAC6 Axis Circumvents Stroma- Mediated Drug Resistance (CAM-DR) and Clonogenicity in Non-Hodgkin B-Cell Lymphomas

Abstract 5094

A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, we demonstrate that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymph node stromal cells, follicular dendritic cells (FDCs), confers drug resistance, enhances lymphoma cell clonogenicity, and is associated with induction of histone deacetylase 6 (HDAC6). Furthermore, stroma down-regulated miR-548m contributes to HDAC6 up-regulation, and HDAC6 is a key determinant for FDC-mediated lymphoma cell survival and colony formation. We further showed that stroma-mediated drug resistance and clonogenic growth are reversed by enforced expression of miR-548m and inhibition of HDAC6. The HDAC6-selective inhibitor tubastatin significantly enhances cell death, abolishes cell adhesion-mediated drug resistance, and suppresses clonogenicity and lymphoma growth suppression ex vivo and in vivo. Together, these data suggest that the lymphoma–stroma interaction in lymph node microenvironment directly impacts the biology of lymphoma through epigenetic regulation of miRNA and HDAC, with HDAC6 as a potential therapeutic target to overcome drug resistance in MCL and other B-cell lymphomas.