Somatic hypermutation of the B cell receptor genes B29 (Igbeta, CD79b) and mb1 (Igalpha, CD79a)

Abstract

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.

Figure 1

Distribution of B29 and mb1 mutations in B cell lymphomas and myelomas. (a) Mutations in B29 were located across the length of the gene but occurred more often in two regions (nt 774–2517 and 2958–3336). The transcriptional start site is located at nt 281. (b) mb1 mutations were found predominantly within ≈2.5 of the +1 (nt 785–3054). Transcription begins at nt 671. The regions of B29 and mb1 containing the majority of mutations are highlighted in yellow. The most densely mutated clusters of the B29 (774–1293 and 2958–3336) and mb1 (785–2389) genes are in boxes. Mutations located within SHM hotspots are shown in red, mutations found outside of hotspots are shown in blue; brackets indicate a larger deletion. Multiple mutations occurring at the same nucleotide are indicated by the height of the bar.