Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor B pathways

Abstract

There is increasing evidence that stromal cell interactions are required for the survival and drug resistance of several types of B-cell malignancies. There is relatively little information regarding the role of the bone marrow/lymphoid microenvironment in the pathogenesis of mantle cell lymphoma. In this study we investigated the interaction of primary mantle cell lymphoma cells with stromal cells in an ex vivo co-culture system. The murine stromal cell line MS-5 and human bone marrow mesenchymal stromal cells were each co-cultured with primary mantle cell lymphoma cells for up to 7 months. Mantle cell lymphoma cultures alone or combined with human stromal cells were analyzed for cell number, cell migration, nuclear factor-κB activation and drug resistance. Co-culture of mantle cell lymphoma cells and human stromal cells results in the survival and proliferation of primary mantle cell lymphoma cells for at least 7 months compared to mantle cell lymphoma cells cultured alone. Mantle cell lymphoma-human stromal cell interactions resulted in activation of the B-cell activating factor/nuclear factor-κB signaling axis resulting in reduced apoptosis, increased mantle cell lymphoma migration and increased drug resistance. Direct mantle cell lymphoma-human stromal cell interactions support long-term expansion and increase the drug-resistance of primary mantle cell lymphoma cells. This is due in part to activation of the canonical and non-canonical nuclear factor κB pathways. We also demonstrated the ability of B-cell activating factor to augment CXCL12- and CXCL13-induced cell migration. Collectively, these findings demonstrate that human stromal cell-mantle cell lymphoma interactions play a pivotal role in the pathogenesis of mantle cell lymphoma and that analysis of mantle cell lymphoma-human stromal cell interactions may help in the identification of novel targets for therapeutic use.