Genetic pathway to recurrent chromosome translocations in murine lymphoma involves V(D)J recombinase

Chromosome translocations involving antigen receptor loci are a genetic hal lmark of non-Hodgkin's lymphomas in humans. Most commonly, these translocat ions result in juxtaposition of the immunoglobulin heavy-chain (IgH) locus with one of several cellular proto-oncogenes, leading to deregulated oncoge ne expression. The V(D)J recombinase, which mediates physiologic rearrangem ents of antigen receptor genes, may play a mechanistic role in some lymphom a translocations, although evidence is indirect. A high incidence of B-line age lymphomas has been observed in mice with severe combined immunodeficien cy (SCID) and p53-null mutations. We show that these tumors are characteris tic of the pro-B-cell stage of development and that they harbor recurrent t ranslocations involving chromosomes 12 and 15. Fluorescence in situ hybridi zation (FISH) shows retention of IgH sequences on the derivative chromosome 12, implying that breakpoints involve the IgH locus. Pro-B-cell lymphomas were suppressed in SCIDp(53-/-) mice by a Rag-2-null mutation, demonstratin g that DNA breaks generated during V(D)J recombination are required for onc ogenic transformation, and suggesting that t(12;15) arise during attempted IgH rearrangement in pro-B cells. These studies indicate that the oncogenic potential inherent in antigen receptor diversification is controlled in vi vo by efficient rejoining of DNA ends generated during V(D)J recombination and an intact cellular response to DNA damage.