V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locusin follicular lymphoma

Using DNA fiber fluorescence in-situ hybridization (FISH) and 3-color inter phase FISH, 2 cases of follicular lymphoma were identified in which the BCL 2 gene was excised from 18q21 and inserted into the immunoglobulin heavy ch ain (IGH) locus at 14q32, Both the insertion breakpoint at 14q32 and the de letion breakpoint at 18q21 were cloned using inverse polymerase chain react ion. Sequence analysis showed that the JH sequences were juxtaposed to the 5'-side of BCL2, and the DH sequences were juxtaposed to the 3'-side of BCL 2, There were breakpoints at both the JH and DH recombination signal sequen ces, and N-nucleotides were present at all breakpoint junctions. At the BCL 2 locus, the 3'-breakpoints in both cases were localized at exactly the sam e nucleotide position, 6.2 kilobase downstream of the major breakpoint regi on, directly adjacent to a complete cryptic recombination signal sequence ( RSS) consisting of a heptamer, a nonamer, and a 23-base pair (bp) spacer. T he BCL2 5'-breakpoints were approximately 600 bp upstream of the gene, with in the CA repeats, Although less evident than for the BCL2 3'-breakpoints, cryptic RSSs were also identified at these breakpoints, with a 12-bp spacer . On the basis of structural characteristics of these rearrangements, a mod el is proposed in which the BCL2 gene is deleted from its locus by recombin ation activation gene-1/-2 (RAG-1/-2)-mediated excision, The gene is subseq uently inserted into the recombining IGH locus, a process involving the for mation of hybrid joints between the IGH coding ends and the BCL2 signal end s. (C) 2000 by The American Society of Hematology.