Leukemia and lymphoma: a cost of doing business for adaptive immunity

According to the old adage, "you don't get something for nothing."This is certainly the case for the novel genetic mechanisms involved in adaptive immunity-V(D)J recombination, class-switch recombination (CSR), and somatic hypermutation (SHM).These mechanisms allow animals to respond with great specificity to a seemingly limitless array of rapidly evolving microbes and their products while investing a relatively small amount of genetic capacity.The cost, however, is genomic instability and its potential contribution to malignancy.A majority of B-and T-cell leukemias and lymphomas are associated with chromosomal abnormalities that bear the hallmarks of aberrant V(D)J or class-switch recombination.In addition, there are examples of B-cell lymphomas with point mutations in proto-oncogenes consistent with a role for SHM.Recent work has led to an increasingly detailed understanding of the biochemistry of V(D)J recombination, CSR, and SHM.Attention is now being focused on precisely how these reactions contribute to genomic instability and cancer.A report by Reddy et al. (2006) in this issue of Genes & Development describes the use of a novel assay to measure the frequency of DNA transposition that occurs as a byproduct of V(D)J recombination.This and other approaches should allow for the identification of conditions that predispose people to leukemia and lymphoma and the genetic pathways that minimize this risk. Novel mechanisms regulating antigen receptor genes in lymphocytesUnlike any other genes in metazoans, immunoglobulin (Ig) and T-cell receptor (TCR) genes are encoded in segments that must be recombined during B-and T-cell development to generate complete genes (Jung and Alt 2004).In the murine Ig heavy-chain (HC) locus, for example, there are ∼110 V H gene segments, 13 D H gene segments, and four J H gene segments dispersed over ∼2.5 Mb of subtelomeric DNA on chromosome 12.Each re-1