Molecular analysis of bcl-1/IgH junctional sequences in mantle cell lymphoma: potential mechanism of the t(11;14) chromosomal translocation

Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation t hat juxtaposes the bcl-1 locus to immunoglobulin (Ig) gene sequences and le ads to deregulation of cyclin D1 gene, t(11;14) is thought to result from a n error of the recombinase during D-TH Ig gene assembly; however, data on t he underlying mechanism and candidate recombination-targeting motifs in the major translocation cluster (MTC) of the bcl-1 gene are lacking. bcl-1/IgH junctional sequences from seven MCL patients were amplified by PC R using primers targeting MTC and J(H) sequences on chromosomes 11q13 and 1 4q32, respectively. PCR products were directly sequenced and junctional seq uences were searched for homology to known germline D genes. bcl-t MTC brea kpoints were searched for the presence of possible recombination target mot ifs; heptamers, nonamers, binding sequence of the bp45 nuclease, x-like seq uences and D gene segments. bcl-1/J(H) junctions were found to bear homology to D gene segments (DLR3, DM and DIR5) in 3/7 MCL samples. A computer-based search in previously publ ished and/or submitted to GenBank bcl-1/J(H) junctional sequences identifie d homology to D genes in 1/4 MCL tumour samples and 1/4 MCl cell lines; DXP 4 or D23/7 and DHQ52 or D22/21 or DXP5, respectively. The MTC locus contain ed motifs with homology to bp45 nuclease binding sequence, x-like sequences , heptamers/nonamers, D-like DIR genes and nonhomologous recombination shor t (6 bp) DNA sequences. The above data indicate that the t(11;14) translocation in MCL may also occ ur at a more mature stage of B-cell ontogeny than previously thought, i.e. during V-H-to-DJ(H) rearrangement. Various known recombination motifs withi n MTC may contribute to an illegitimate recombination event between bcl-1 a nd DJ(H).