B-cell receptor and Fas-mediated signals for life and death

A series of B-cell lymphoma lines with an immature phenotype has been used as a model system to study molecular events associated with receptor Ligati on-induced death. B-cell receptor (BCR) cross-linking with antibodies to me mbrane IgM (but not with anti-IgD) induces c-Myc downregulation via nuclear factor KB inactivation and p27(Kip1) accumulation in these B lymphomas. An ti-mu-treated cells then undergo G1 arrest and die by apoptosis independent of Fas. Steroids and retinoids similarly downregulate c-Myc and induce apo ptosis in these B cells and synergize with anti-mu. Rescue from apoptosis i nduced by anti-mu or steroids occurs with T-cell signals, Like CD40L, or a broad-range caspase inhibitor, but only CD40L prevents the loss of c-Myc, p 27 accumulation and growth arrest. Both IgM and IgD signaling lead to modul ation of phosphatidylinositol 3-kinase (PI3K) signals, including the activa tion of p70(S6K), but this pathway recovers under anti-IgD treatment. Block ade of the PI3K pathway augments anti-mu-induced death and converts anti-de lta to an apoptotic signal. Resistance to Fas-mediated death may be an impo rtant factor in B-cell transformation in vivo. Many of our panel of lymphom as are insensitive to Fas-mediated death signals, although all can form a d eath-inducing signaling complex (DISC). Additional studies suggest that som e lymphomas can be blocked at the DISC complex by anti-apoptotic proteins, whereas others are inhibited downstream of caspase 8 activation. Anti-Ig tr eatment of a Fas-sensitive line, A20.2J, activated a number of genes whose products may block apoptosis proximally (like FLICE-inhibitory protein (FLI P,)) or at late points, such as bcl-2-family members. Our data suggest that B lymphomas develop multiple pathways of resistance to Fas-mediated signal s during lymphomagenesis, in parr via signaling through the BCR.