Restricting activation-induced cytidine deaminase tumorigenic activity in B lymphocytes.
DNA breaks play an essential role in germinal centre B cells as intermediates to immunoglobulin class switching, a recombination process initiated by activation-induced cytidine deaminase (AID). Immunoglobulin gene hypermutation is likewise catalysed by AID but is believed to occur via single-strand DNA breaks. When improperly repaired, AID-mediated lesions can promote chromosomal translocations (CTs) that juxtapose the immunoglobulin loci to heterologous genomic sites, including oncogenes. Two of the most studied translocations are the t(8;14) and T(12;15), which deregulate cMyc in human Burkitt's lymphomas and mouse plasmacytomas, respectively. While a complete understanding of the aetiology of such translocations is lacking, recent studies using diverse mouse models have shed light on two important issues: (1) the extent to which non-specific or AID-mediated DNA lesions promote CTs, and (2) the safeguard mechanisms that B cells employ to prevent AID tumorigenic activity. Here we review these advances and discuss the usage of pristane-induced mouse plasmacytomas as a tool to investigate the origin of Igh-cMyc translocations and B-cell tumorigenesis.
Casellas
Rafael
R
Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA. casellar@mail.nih.gov
Yamane
Arito
A
Kovalchuk
Alexander L
AL
Potter
Michael
M
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D003564:Cytidine Deaminase / Q000378:metabolism*; D050438:Genes, Immunoglobulin Heavy Chain / Q000276:immunology; D016259:Genes, myc / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010954:Plasmacytoma / Q000235:genetics / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D014178:Translocation, Genetic / Q000276:immunology
D003564:Cytidine Deaminase