Molecular mechanism of the t(14;18)--a model for lymphoid-specific chromosomal translocations.

Abstract

The chromosomal translocation t(14;18) occurs during early B-cell development and juxtaposes the immunoglobulin heavy chain locus (IgH) with the bcl-2 oncogene. Several factors contribute to the translocation mechanism: (1) The rearrangement of the chromosome 14 DH and JH translocation partners has typical features of V(D)J-recombinase-mediated joining with N-segment addition. (2) The bcl-2 major (mbr) and minor (mcr) breakpoint regions as well as their IgH reciprocal counterparts contain recombinatorial sequences related to chi or the minisatellite-core which bind at least one common DNA-binding protein (bp45). Similar elements are found at the breakpoints of other lymphoid-specific translocations like the t(11;14), t(2;8) or the t(4;11). (3) Structural analysis of the bcl-2 mbr indicates that this region may adopt alternative DNA-configurations which can promote recombination and is cleaved by an endogenous nuclease present in early B-cells. The present data suggest that V(D)J-recombinase as well as chi/minisatellite-core mediated recombination contribute to the mechanism and make the t(14;18) a model system for lymphoid-specific reciprocal translocations.