Ongoing hypermutation in the Ig V(D)J gene segments and c-myc proto-oncogene of an AIDS lymphoma segregates with neoplastic B cells at different sites: implications for clonal evolution

• Published in: Human immunology 2000-12, Vol.61 (12), p.1242-1253
• Main Authors: Ikematsu, Hideyuki, Cerutti, Andrea, Zan, Hong, Knowles, Daniel M., Ikematsu, Wataru, Casali, Paolo
• Format: Article
• Language: English
• Subjects: Adult; AIDS-associated Burkitt’s lymphoma; Amino Acid Sequence; Antibody Diversity - genetics; B lymphocytes; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Base Sequence; Binomial Distribution; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Burkitt Lymphoma - genetics; Burkitt Lymphoma - immunology; Burkitt Lymphoma - pathology; c- myc genes; c-Myc gene; Cell Differentiation - genetics; Cell Differentiation - immunology; Clone Cells - immunology; Clone Cells - pathology; Gene Frequency - immunology; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Gene Rearrangement, B-Lymphocyte, Light Chain; Genes, myc - immunology; Humans; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Joining Region - genetics; Immunoglobulin kappa-Chains - genetics; Immunoglobulin Variable Region - genetics; Lymphoma, AIDS-Related - genetics; Lymphoma, AIDS-Related - immunology; Lymphoma, AIDS-Related - pathology; Male; Molecular Sequence Data; Orbital Neoplasms - genetics; Orbital Neoplasms - immunology; Point Mutation; somatic mutations; Testicular Neoplasms - genetics; Testicular Neoplasms - immunology; V(D)J genes
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/S0198-8859(00)00181-6

To investigate the role of somatic Ig hypermutation in the evolution of AIDS-associated B cell lymphomas, we analyzed the Ig V(D)J and c- myc genes expressed by neoplastic B cells in two extranodal sites, testis and orbit, and clonally related cells in the bone marrow. Testis and orbit B cells expressed differentially mutated but collinear V HDJ H, VκJκ and c- myc gene sequences. Shared mutations accounted for 10.2%, 8.4%, and 4.3% of the overall V HDJ H, VκJκ, and c- myc gene sequences. Tumor-site specific V HDJ H, VκJκ, and c- myc mutations were comparable in frequency, and a single point-mutation gave rise to an EcoRI site in the testis c- myc DNA. Both shared and tumor site-specific V HDJ H, VκJκ, and c-myc mutations displayed predominance of transitions over transversions. The “neoplastic” V HDJ H sequence was expressed by about 10 −5 cells in the bone marrow, and contained two of the three orbital, but none of the testicular V HDJ H mutations. The nature and distribution of the Ig V(D)J mutations found in the κ chain suggested a selection by antigen in testis and orbit. Our data suggest that, in AIDS-associated B cell lymphomas, the Ig hypermutation machinery targets V HDJ H, VκJκ, and c- myc genes with comparable efficiency and modalities.