Aberrant B cell receptor signaling from B29 (Ig beta, CD79b) gene mutations of chronic lymphocytic leukemia B cells

Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low o r undetectable surface B cell receptor (BCR) and diminished responses to BC R-mediated signaling. These features suggest that CLL cells may have sustai ned mutations affecting one or more of the BCR proteins required for recept or surface assembly and signal transduction. Loss of expression and mutatio ns in the critical BCR protein B29 (Ig beta, CD79b), are prevalent in CLL a nd could produce the hallmark features of these leukemic B cells. Because p atient CLL cells are intractable to manipulation, we developed a model syst em to analyze B29 mutations. Jurkat T cells stably expressing mu, kappa, an d mb? efficiently assembled a functional BCR when infected with recombinant vaccinia virus bearing wild-type B29. In contrast, a B29 CLL mutant protei n truncated in the transmembrane domain did not associate with mu or mb1 at the cell surface. Another B29 CLL mutant lacking the C-terminal immunorece ptor tyrosine activation motif tyrosine and distal residues brought the rec eptor to the surface as well as wild-type B29 but showed significant impair ment in anti-IgM-stimulated signaling events including mitogen-activated pr otein kinase activation. These findings demonstrate that B29 mutations prev iously identified in CLL patients can affect BCR-dependent signaling and ma y contribute to the unresponsive B cell phenotype in at Finally, the featur es of the B29 mutations in CLL predict that they may be generated by somati c hypermutation.