Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 7, Pages 4126-4131Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0735266100
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Funding
- NCI NIH HHS [R01 CA085841, T32-CA009120-26, T32 CA009120, R01CA85841] Funding Source: Medline
- NIAID NIH HHS [T32-AI07126-26, T32 AI007126] Funding Source: Medline
- NIGMS NIH HHS [R01 GM040185, R01GM40185] Funding Source: Medline
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Somatic hypermutation (SHM), coupled to selection by antigen, generates high-affinity antibodies during germinal center (GC) B cell maturation. SHM is known to affect Bc16, four additional oncogenes in diffuse large B cell lymphoma, and the CD95/Fas 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 mbt (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 829 and mb1 mutations are typical SHM consisting largely of single nucleotide substitutions targeted to hotspots. The 829 and mb1 mutations appear at frequencies similar to those of othernon-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, 829 mutations displayed a bimodal distribution resembling the CD95/Fas gene, in which promoter distal mutations conferred resistance to apoptosis. Distal 829 mutations in the cytoplasmic domain may contribute to B cell survival by limiting BCR signaling. 829 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, mbt, and Ig chains in the BCR.
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