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CD20 is a B-cell differentiation antigen and known to induce apoptosis in Burkitt's lymphoma/leukemia (BL) cells upon antibody-mediated crosslinking. We examined the biological effect of CD20 crosslinking on BL cell lines and observed that apoptosis induction is accompanied by activation of multiple caspases, including caspase-8, -9, -3, -2, and -7. Further investigation revealed a clear synergism between apoptosis mediated by CD20 and by B-cell antigen receptor (BCR). Examination of the effect of simultaneous crosslinking of other cell surface molecules with crosslinking of CD20 or BCR on apoptosis induction showed that these molecules had either a synergistic or inhibitory effect on induction of apoptosis. It is worth noting that some molecules had a different effect on CD20- and BCR-mediated apoptosis. Simultaneous crosslinking of the molecules CD10, CD22, CD72, and CD80 inhibited BCR-mediated apoptosis, but enhanced CD20-mediated apoptosis. Further studies revealed that regulation of CD20-induced apoptosis by other costimulatory molecules is achieved by modification of caspase activation. CD20-mediated apoptosis in BL cells may provide not only a model for understanding the mechanism regulating clonal selection of B cells but a new therapeutic strategy for BL patients.