A role for secondary V(D)J recombination in oncogenic chromosomal translocations?

Abstract

Chromosomal translocations are hallmarks of certain lymphoproliferative disorders. Indeed, in many leukemias and lymphomas, translocations are the transforming event that brings about malignancy. Recurrence of the immunoglobulin (Ig) and T-cell receptor (Tcr) loci at the breakpoints of oncogenic chromosomal translocations has led to speculation that the lymphocyte-specific process of V(D)J rearrangement, which is necessary for the generation of functional Ig and TCR antigen receptors on B and T lymphocytes, mediates translocation. Recent studies have led to a fuller understanding of the molecular mechanisms of V(D)J rearrangement and have revealed that the V(D)J recombinase possesses latent transposase activity. These studies have led to plausible models of illegitimate V(D)J recombination producing chromosomal translocations consistent with those present in lymphomas and leukemias. Errors of V(D)J recombination may even generate lymphomas with the phenotypes of mature cells. For example, follicular and Burkitt's lymphomas have been classified by phenotype and somatic genotype as malignant germinal center (GC) B or post-GC B cells. The GC is a site of affinity maturation where B cells undergo V(D)J hypermutation and Ig class switch; in addition, much evidence has accumulated to suggest that GC B cells may also support secondary V(D)J recombination. Interestingly, all three of these elements, genomic plasticity, mutation, and translocation breakpoints near switch sites or recombinational elements, are characteristic of certain lymphomas. The high frequency of lymphomas carrying these GC markers suggests that the GC reaction may play a significant role in lymphomagenesis.