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

G. B. Carey, D. Donjerkovic, C. M. Mueller, S. Liu, J. A. Hinshaw, L. Tonnetti, W. Davidson, D. W. Scott*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

42 Scopus citations


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 withanti-IgD) induces c-Myc downregulation via nuclear factor κB inactivation and p27(kip)1 accumulation in these B lymphomas. Anti-μ-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 withanti-μ. Rescue from apoptosis induced by anti-μ 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(S)6(K), but this pathway recovers under anti-IgD treatment. Blockade of the PI3K pathway augmentsanti-μ-induced death and converts anti-δ 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 areinsensitive to Fas-mediated death signals, although all can form adeath-inducing signaling complex (DISC). Additional studies suggest that some lymphomas can be blocked at the DISC complex byanti-apoptotic proteins, whereas others are inhibited downstream ofcaspase 8 activation. Anti-Ig treatment of a Fas-sensitive line,A20.2J, activated a number of genes whose products may blockapoptosis proximally (like FLICE-inhibitory protein (FLIP(L))) orat 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.

Original languageEnglish
Pages (from-to)105-115
Number of pages11
JournalImmunological Reviews
StatePublished - 2000
Externally publishedYes


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