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 CD95͞Fas 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 (Ig, CD79b) and mb1 (Ig␣, 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 CD95͞Fas 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.
Bcell malignancies account for 90-95% of all adult leukemias and lymphomas (1). The majority of these malignant B cells carry somatic hypermutation (SHM) in their Ig variable (IgV) regions, identifying them as germinal center (GC) or post-GC in origin (1). Originally thought to be confined to IgV regions, genes translocated into the Ig locus, or transgenes under the control of Ig enhancers, SHM is now known to also mutate non-Ig genes. Mistargeted SHM was first identified in Bcl6 in approximately half of GC-derived malignancies (2) and a minor fraction of normal GC-derived B cells (3). The CD95͞Fas gene was subsequently shown to be mutated in a limited set of normal and malignant post-GC B cells (4). Recently the Pax5, Pim1, RhoH͞ TTF, and germ-line c-myc oncogenes were reported to be hypermutated, but only in diffuse large B cell lymphoma (DL-BCL) (5). With the exception of CD95͞Fas, all known hypermutated non-Ig genes undergo translocations into the Ig locus. SHM of the four oncogenes in DLBCL is predicted to reflect selection (5), as shown for the CD95͞Fas death domain mutations associated with resistance to apoptosis (6).We (7) and others (8, 9) previously reported multiple B29 coding region mutations in chronic lymphocytic leukemia (CLL) cells with low or undetectable surface B cell receptor (BCR). We have also demonstrated that selected CLL-B29 mutations reproduced the low BCR surface expression and diminished BCR signaling that are the hallmarks of CLL (10). The features of these CLL-B29 mutations led us to predict that they were generated by SHM. Here we report tha...
