Diversity and somatic hypermutation of the Ig V HDJ H, VκJκ, and VλJλ Gene Segments in Lymphoma B cells: Relevance to the origin of the neoplastic B cell clone

Abstract

Burkitt’s lymphoma (BL) is a malignancy of B cells characterized by chromosomal translocations involving the immunoglobulin (Ig) and c-MYC gene loci. To address the putative role of antigen in the clonal expansion of these neoplastic B cells, we analyzed the V HDJ H and V LJ L gene segments expressed by the established cell lines derived from six endemic BL and six sporadic BL. Eight BL cell lines used genes of the V H3 family, two of the V H4, and two of the V H1. Eight V L chains were κ (four members of the Vκ3, two of the Vκ1, and two of the Vκ2 subgroups) and four λ (three members of the Vλ1 and one of the Vλ3 subgroup). The V H gene utilization was stochastic ( i.e., it reflected the relative representation of the different V H gene family members in the human haploid genome). In contrast, the V L gene utilization was skewed toward the overutilization of the Vκ3 and Vλ1 gene subgroups. When compared with those of the respective germline genes, the sequences of the expressed Ig V(D)J genes displayed nucleotide differences that resulted from somatic hypermutation. In three endemic and three sporadic BL cells, nucleotide changes yielding amino acid substitutions segregated within the complementarity determining region, indicating the application of a positive pressure for replacement mutations and suggesting that these neoplastic lymphocytes underwent a process of clonal selection driven by antigen, perhaps emerging from or transitioning through germinal centers.