V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma.
Using DNA fiber fluorescence in-situ hybridization (FISH) and 3-color interphase FISH, 2 cases of follicular lymphoma were identified in which the BCL2 gene was excised from 18q21 and inserted into the immunoglobulin heavy chain (IGH) locus at 14q32. Both the insertion breakpoint at 14q32 and the deletion breakpoint at 18q21 were cloned using inverse polymerase chain reaction. 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 BCL2. There were breakpoints at both the JH and DH recombination signal sequences, and N-nucleotides were present at all breakpoint junctions. At the BCL2 locus, the 3'-breakpoints in both cases were localized at exactly the same nucleotide position, 6. 2 kilobase downstream of the major breakpoint region, directly adjacent to a complete cryptic recombination signal sequence (RSS) consisting of a heptamer, a nonamer, and a 23-base pair (bp) spacer. The BCL2 5'-breakpoints were approximately 600 bp upstream of the gene, within 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 model is proposed in which the BCL2 gene is deleted from its locus by recombination activation gene-1/-2 (RAG-1/-2)-mediated excision. The gene is subsequently inserted into the recombining IGH locus, a process involving the formation of hybrid joints between the IGH coding ends and the BCL2 signal ends. (Blood. 2000;96:1947-1952)
Vaandrager
J W
JW
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Schuuring
E
E
Philippo
K
K
Kluin
P M
PM
D001483:Base Sequence; D003001:Cloning, Molecular; D004254:DNA Nucleotidyltransferases / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D015321:Gene Rearrangement; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D045567:VDJ Recombinases
D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D019253:Proto-Oncogene Proteins c-bcl-2; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases