Aberrant B cell receptor signaling from B29 (Igbeta, CD79b) gene mutations of chronic lymphocytic leukemia B cells.
Chronic lymphocytic leukemia (CLL) B cells characteristically exhibit low or undetectable surface B cell receptor (BCR) and diminished responses to BCR-mediated signaling. These features suggest that CLL cells may have sustained mutations affecting one or more of the BCR proteins required for receptor surface assembly and signal transduction. Loss of expression and mutations in the critical BCR protein B29 (Igbeta, CD79b), are prevalent in CLL and could produce the hallmark features of these leukemic B cells. Because patient CLL cells are intractable to manipulation, we developed a model system to analyze B29 mutations. Jurkat T cells stably expressing micro, kappa, and mb1 efficiently assembled a functional BCR when infected with recombinant vaccinia virus bearing wild-type B29. In contrast, a B29 CLL mutant protein truncated in the transmembrane domain did not associate with mu or mb1 at the cell surface. Another B29 CLL mutant lacking the C-terminal immunoreceptor tyrosine activation motif tyrosine and distal residues brought the receptor to the surface as well as wild-type B29 but showed significant impairment in anti-IgM-stimulated signaling events including mitogen-activated protein kinase activation. These findings demonstrate that B29 mutations previously identified in CLL patients can affect BCR-dependent signaling and may contribute to the unresponsive B cell phenotype in CLL. Finally, the features of the B29 mutations in CLL predict that they may be generated by somatic hypermutation.
Gordon
M S
MS
Molecular Biology Institute, Department of Microbiology, Division of Immunology/Rheumatology, University of California School of Medicine, Los Angeles, CA 90095, USA.
Kato
R M
RM
Lansigan
F
F
Thompson
A A
AA
Wall
R
R
Rawlings
D J
DJ
D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D051925:CD79 Antigens; D005434:Flow Cytometry; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D051925:CD79 Antigens; C497883:CD79B protein, human; D007075:Immunoglobulin M; D011948:Receptors, Antigen, T-Cell