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
ligation induced death. B-cell receptor (BCR) cross-linking with
antibodies to membrane
IgM (but not with
anti IgD) induces c-Myc downregulation via
nuclear factor kappaB inactivation and p27(Kip1) accumulation in these B
lymphomas. Anti-mu-treated cells then undergo G1 arrest and die by apoptosis independent of Fas.
Steroids and
retinoids similarly downregulate c-Myc and induce apoptosis in these B cells and synergize with anti-mu. Rescue from apoptosis induced 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, p27 accumulation and growth arrest. Both
IgM and
IgD signaling lead to modulation of
phosphatidylinositol 3-kinase (PI3K) signals, including the activation of p70(S6K), but this pathway recovers under
anti-IgD treatment. Blockade of the PI3K pathway augments anti-mu-induced death and converts anti-delta to an apoptotic signal. Resistance to Fas-mediated death may be an important factor in B-cell transformation in vivo. Many of our panel of
lymphomas are insensitive to Fas-mediated death signals, although all can form a death-inducing signaling complex (DISC). Additional studies suggest that some
lymphomas can be blocked at the DISC complex by
anti-apoptotic proteins, whereas others are inhibited downstream of
caspase 8 activation. Anti-Ig treatment of a Fas-sensitive line, A20.2J, activated a number of genes whose products may block apoptosis proximally (like
FLICE-inhibitory protein (FLIP1)) or at late points, such as bcl-2-family members. Our data suggest that B
lymphomas develop multiple pathways of resistance to Fas-mediated signals during lymphomagenesis, in part via signaling through the BCR.