Anti-CD20- and B-cell Receptor-mediated Apoptosis: Evidence for Shared Intracellular Signaling Pathways
2000
Clinical
administration of the anti-CD20 antibody IDEC-C2B8 can induce remission
of low-grade B-cell lymphoma. Whereas it has been suggested that the
main mechanisms of action are complement-mediated and
antibody-dependent cell-mediated cytotoxicity, we demonstrate that
monoclonal antibody IDEC-C2B8 is a strong inducer of apoptosis in
CD20-positive B-cell lymphoma cell lines reflecting different stages of
lymphomagenesis. Thus, CD20-dependent apoptosis was inducible in human
surface IgM-positive Burkitt’s lymphoma cell lines as well as in more
mature surface IgM-negative B-cell lymphoma cell lines carrying the
t(14;18) translocation. Furthermore, in Burkitt’s lymphoma cell lines,
we observed a striking correlation between anti-CD20- and B-cell
receptor-mediated apoptosis with regard to sensitivity toward the
apoptotic stimuli and the execution of the apoptotic pathway. Thus,
induction of anti-CD20- or B-cell receptor-mediated apoptosis involved
rapid up-regulation of the proapoptotic protein Bax. In addition, we
show similar changes in the mRNA expression level of two early response
genes, c-myc and Berg36, as well as activation of the
mitogen-activated protein kinase family members p44 (extracellular
signal-regulated kinase 1) and p42 (extracellular signal-regulated
kinase 2) and activation of activator protein 1 (AP-1) DNA
binding activity. These data support our hypothesis that both pathways
are mediated in part by the same signal-transducing molecules. These
results might help explain the resistance and regression of lymphomas
to IDEC-C2B8 and give new insights in the signaling cascade
after CD20 ligation.
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