Although adult murine B cells can be stimulated to proliferate by IgM receptor cross-linking, we and others have shown that these cells will undergo apoptosis in vitro in a dose-, time- and temperature-dependent manner with polyclonal but not monoclonal antl-lgM. To test the role of c-myc and cell cycle progression in B cell apoptosis, we examined normal, Sp6 antl-TNP Ig and Eμ-myc transgenic splenocytes for receptor-mediated apoptosis in vitro. In normal mice, both spontaneous and anti-lgM-lnduced programmed cell death were specifically blocked by antisense oligodeoxynucleotides for the c-myc proto-oncogene, whereas nonsense myc oligonucleotides and irrelevant oligonucleotides had only a minor effect. Similarly, TNP-dextran-induced apoptosis in Sp6 antl-TNP transgenics was inhibited by antisense c-myc. This effect was not due to the mitogenic effects of unmethylated CpG-contalnlng sequences because ones lacking this motif, as well as methylated oligonucleotides containing this motif, prevented apoptosis, and mitogenic doses of lipopolysaccharlde failed to Inhibit anti-lgM-driven cell death. Importantly, antisense c-myc also prevented the anti-lgM-lnduced increase in myc protein species. Moreover, spontaneous apoptosis in vitro was exaggerated in Eμ-myc transgenic B cells. To examine the role of CD45 in anti-lgM-induced apoptosis, we treated spleen cells from CD45 knockout mice, which do not proliferate with anti-IgM, and found that B cells from these underwent apoptosis normally despite the lack of entry into S. These data suggest that anti-IgM driven apoptosis does not require CD45. Rather, apoptosis may be due to an overexpression of myc protein in the absence of signals which can drive B cells productively Into S, but the failure to proliferate normally is insufficient for apoptosis to occur.