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

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.