Somatic hypermutation of the B cell receptor genes B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a).
Somatic hypermutation (SHM), coupled to selection by antigen, generates high-affinity antibodies during germinal center (GC) B cell maturation. SHM is known to affect Bcl6, four additional oncogenes in diffuse large B cell lymphoma, and the CD95Fas gene and is regarded as a major mechanism of B cell tumorigenesis. We find that mutations in the genes encoding the B cell receptor (BCR) accessory proteins B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a) occur as often as Ig genes in a broad spectrum of GC- and post-GC-derived malignant B cell lines, as well as in normal peripheral B cells. These B29 and mb1 mutations are typical SHM consisting largely of single nucleotide substitutions targeted to hotspots. The B29 and mb1 mutations appear at frequencies similar to those of other non-Ig genes but lower than Ig genes. The distribution of mb1 mutations followed the characteristic pattern found in Ig and most non-Ig genes. In contrast, B29 mutations displayed a bimodal distribution resembling the CD95Fas gene, in which promoter distal mutations conferred resistance to apoptosis. Distal B29 mutations in the cytoplasmic domain may contribute to B cell survival by limiting BCR signaling. B29 and mb1 are mutated in a much broader spectrum of GC-derived B cells than any other known somatically hypermutated non-Ig gene. This may be caused by the common cis-acting regulatory sequences that control the requisite coexpression of the B29, mb1, and Ig chains in the BCR.
Gordon
Melinda S
MS
Department of Microbiology, Immunology, and Molecular Genetics, and David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
Kanegai
Cindy M
CM
Doerr
Jeanette R
JR
Wall
Randolph
R
D015703:Antigens, CD / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D051925:CD79 Antigens; D002460:Cell Line; D002478:Cells, Cultured; D005803:Genes, Immunoglobulin; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology; D009154:Mutation; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D051925:CD79 Antigens; C497881:CD79A protein, human; C497883:CD79B protein, human; D011947:Receptors, Antigen, B-Cell