B Cell Receptor (BCR) Signal Pathways Confer Microenvironment-Mediated Drug Resistance and Are Promising Therapeutic Targets for B Cell Lymphomas

Abstract 4918

Despite intensive efforts in developing new therapies, B-cell lymphoma remains essentially incurable with standard therapeutic approaches. Dynamic interactions between the lymphoma cell and its microenvironment play a critical role in lymphoma development and response to therapy. There is accumulating evidence pointing to an essential role of BCR signaling in B-cell lymphomas. Recently, inhibitors of BCR signaling have become an area of substantial clinical interest. We therefore studied the role of BCR signal pathways in stroma-mediated lymphoma cell survival. We demonstrated that adhesion of the various B-cell lymphoma cell lines to lymph node stromal cells enhanced activation of BCR signaling pathways: activation of phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (Btk) and extracellular signal-regulated kinase (ERK) pathways. Inhibition of Btk by PCI 32765 or PI3K by CAL101 significantly blocked BCR signal pathways, triggered lymphoma cell apoptosis and overcame stroma-mediated drug resistance. Furthermore, targeting BCR signal pathway disrupted microenvironmental stroma-lymphoma interaction through regulation of CXCR4 expression. Collectively, these data support that BCR activation not only controls intrinsic survival pathway related to B lymphoma cell but also regulates stroma-mediated extrinsic lymphoma cell survival as well as lymphoma cell homing and interplay with its microenvironment. As a result, this study suggests that targeting BCR signal pathway molecules is a promising therapeutic strategy to lymphoma therapy.