title: Alternative end-joining in follicular lymphomas' t(14;18) translocation.
abstract: T(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between the BCL2 proto-oncogene and the IGH locus during the D(H) to J(H) joining phase of V(D)J recombination in early B cells. Analysis of the breakpoint junctions suggests that translocation derives from the fusion between normal V(D)J recombination intermediates at the IGH locus and non-V(D)J-mediated broken-ends at the BCL2 locus. So far, BCL2 broken-ends have only been observed fused to coding-ends, raising questions concerning the molecular constraints of the illegitimate joining process. Using a combination of genome walking and long-range PCR assays, we describe in this report that in 4.5% (2/44) of the t(14;18), one of the BCL2 broken-ends is fused to a signal-end. The formation of these J(H)RSS/BCL2 junctions provides direct evidence that BCL2 broken-ends are capable of joining to both products of V(D)J recombination, suggesting their presence in the RAG-mediated post-cleavage complex. In addition, junctions generated by this alternative end-joining do not involve deletion of the chromosome 14 intervening sequences generally lost in the standard translocation, providing a unique opportunity to investigate the rearrangement status of this region in the translocated IGH allele. In both cases, a DJ(H) rearrangement could be detected 5' of the J(H)-RSS/BCL2 junction. These findings, together with the previously reported bias towards the most external D(H) and J(H) segments in standard breakpoints, strongly suggest that t(14;18) preferentially occurs during an attempted secondary D(H) to J(H) rearrangement. This unusual and restricted window of differentiation opens intriguing questions concerning the etiology of the translocation.
authors.affiliation: Department of Internal Medicine I, Division of Hematology, University of Vienna, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Marculescu
authors.forename: T
authors.initials: T
authors.lastname: Le
authors.forename: S
authors.initials: S
authors.lastname: Böcskör
authors.forename: G
authors.initials: G
authors.lastname: Mitterbauer
authors.forename: A
authors.initials: A
authors.lastname: Chott
authors.forename: C
authors.initials: C
authors.lastname: Mannhalter
authors.forename: U
authors.initials: U
authors.lastname: Jaeger
authors.forename: B
authors.initials: B
authors.lastname: Nadel
mesh_terms: D001483:Base Sequence; D019457:Chromosome Breakage; D016386:Chromosome Walking; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics / Q000648:ultrastructure*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics / Q000648:ultrastructure*; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D019254:Genes, bcl-2; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007133:Immunoglobulin Joining Region / Q000235:genetics; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D014178:Translocation, Genetic / Q000235:genetics*; D045567:VDJ Recombinases
chemical_list: D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases