Stromal cells are an essential component of the bone marrow microenvironment that regulate or supports
tumor survival. In this study we therefore studied the role of stromal cells in
lymphoma cell survival. We demonstrated that adhesion of the
B-cell lymphoma cell lines SUDH-4 and 10 to bone marrow stroma inhibited
mitoxantrone-induced apoptosis. This adhesion-dependent inhibition of
mitoxantrone-induced apoptosis correlated with decreased activation of caspases-8 and 9, and cleavage of
caspase 3 and PARP. Electrophoretic mobility shift assays (EMSA) analysis demonstrated significantly increased
NF-kappaB binding activity in
lymphoma cells adhered to stroma cells compared to
lymphoma cells in
suspension. This
DNA binding activity could be attributed to cell adhesion-mediated proteolysis of the
NF-kappaB precursor, p100 (NF-kappaB2). This resulted in the generation of active p52, which translocated to the nucleus in complex with p65 and RelB. Coculture with stromal cells also induced expression of the
NF-kappaB-regulated anti-apoptotic molecules, XIAP, cIAP(1) and cIAP(2). Inhibition of
NF-kappaB significantly suppressed HS-5-induced protection against apoptosis in
lymphoma cell lines as well as in primary
lymphoma cells. Thus, bone marrow stroma protects
B-cell lymphoma cells against apoptosis, at least in part through activation of
NF-kappaB dependent mechanism involving up-regulation of
NF-kappaB regulated antiapoptotic
proteins. Consequently, this study suggests a new approach to decrease the resistance of
lymphoma to
chemotherapy.