AbstractEngagement of mIgM induces G1 arrest and apoptosis in immature B cells. The biochemical mechanism(s) regulating the cell death process are poorly understood. Cross‐linking of CD72 (a B cell co‐receptor) with anti‐CD72 antibody was shown to protect B cells from apoptosis. We investigated the molecular mechanism involved in apoptosis preventing signaling mediated by CD72 ligation using a derivative (WEHIδ) of the WEHI231 cell line which is representative of immature B cells. Apoptotic WEHIδ cells following cross‐linking of mIgM demonstrate a dramatic loss of c‐Myc protein after transient up‐regulation. In contrast, pre‐ligation of CD72 was able to sustain c‐Myc expression after transient up‐regulation. Cross‐linking of mIgM of WEHIδ cells causes accumulation of the Cdk inhibitor, p27Kip1. CD72 pre‐ligation was shown to inhibit the accumulation of p27Kip1 protein. Moreover, NF‐κB activity was not suppressed in WEHIδ cells after mIgM cross‐linking when the cells were pre‐treated with anti‐CD72 antibody. These results strongly suggest that the apoptosis preventing signal evoked by CD72 ligation is delivered through the pathway of NF‐κB, c‐Myc, p27Kip1 and cyclin.