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

Abstract

Summary.Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation that juxtaposes the bcl-1 locus to immunoglobulin (Ig) gene sequences and leads to deregulation of cyclin D1 gene. t(11;14) is thought to result from an error of the recombinase during D-J H Ig gene assembly; however, data on the 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 PCR using primers targeting MTC and J H sequences on chromosomes 11q13 and 14q32, respectively. PCR products were directly sequenced and junctional sequences were searched for homology to known germline D genes. bcl-t MTC breakpoints were searched for the presence of possible recombination target motifs; heptamers, nonamers, binding sequence of the bp45 nuclease, x-like sequences 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 published and/or submitted to GenBank bcl-1/J H junctional sequences identified homology to D genes in 1/4 MCL tumour samples and 1/4 MCl cell lines; DXP4 or D23/7 and DHQ52 or D22/21 or DXP5, respectively. The MTC locus contained motifs with homology to bp45 nuclease binding sequence, x-like sequences, heptamers/nonamers, D-like DIR genes and nonhomologous recombination short (6 bp) DNA sequences. The above data indicate that the t(11;14) translocation in MCL may also occur 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 within MTC may contribute to an illegitimate recombination event between bcl-1 and DJ H .

V(D)J recombinase mediated inter-chromosomalHPRT alterations at cryptic recombination signal sequences in peripheral human T cells

“…The 3' signal joint formed in ETS 59 M3 is analogous to the observed signal joints formed in t(7,9) translocations at a Ψ RSS in patients with T ALL (Marculescu, et al, 2003). Similar V(D)J recombinase mediated signal ended products generated by cleavage at Ψ RSS have also been implicated in many other translocations observed in T and B cell leukemia and lymphoma (Davila, et al, 2001;Marculescu, et al, 2002;Marculescu, et al, 2003;Raghavan, et al, 2004;Stamatopoulos, et al, 1999;Tycko and Sklar, 1990). In addition, this insertion is analogous to the pathogenic insertion of a IgH signal ended molecule into 11q13 observed in patients with multiple myeloma (Gabrea, et al, 1999).…”

“…There is strong evidence that V(D)J recombinase mediates many of these leukemogenic events during immune development through cleavage at immune RSSs, Ψ RSSs and at various breakpoint cluster regions with specific DNA conformation (Breit, et al, 1993;Davila, et al, 2001;Marculescu, et al, 2003;Raghavan, et al, 2001;Raghavan, et al, 2004;Stamatopoulos, et al, 1999;Tycko and Sklar, 1990). This presents the challenge of regulating aberrant events during the development of a diverse immune system.…”

“…These rearrangements outside of the immune loci have potentially deleterious consequences. Of clinical importance is that V(D)J recombinase mediated rearrangements at Ψ RSSs include deletions, insertions, and translocations, that have been observed in malignant lymphoid cells (Davila, et al, 2001;Marculescu, et al, 2003;Rowley, 1999;Stamatopoulos, et al, 1999;Tycko and Sklar, 1990). Many of these translocations involve rearrangements with TCR and Ig gene segments at one end that appear to be targeted to specific breakpoint cluster regions or non-RAG1/2 generated ends (Davila, et al, 2001).…”

Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire

“…Moreover, since CDR3 formation might play a pivotal role in antigen binding and selection, our analysis of D gene reading frames (RF) in B cell lymphoid malignancies revealed a consistent pattern of usage in RF2 and RF3 both for MM and FL; 70 it is noteworthy that similar RF usage was observed in D gene segments paricipating in the t(14;18) and t(11;14) chromosomal translocations. 71,72 Generally, the nature of somatic mutations in hypermutating B cells indicates a preference for transitions over transversions with purines being preferentially targeted over pyrimidines, suggesting strand bias; mutations are concentrated mainly in CDRs and most often are single nucleotide substitutions. [72][73][74][75][76] However, investigators have reported deletions or insertions of base stretches of varying length in hypermutating B cells and have concluded that this is a byproduct of the somatic hypermutation machinery within the GC rather than a result of V(D)J recombination in earlier stages of B cell ontogeny.…”

“…71,72 Generally, the nature of somatic mutations in hypermutating B cells indicates a preference for transitions over transversions with purines being preferentially targeted over pyrimidines, suggesting strand bias; mutations are concentrated mainly in CDRs and most often are single nucleotide substitutions. [72][73][74][75][76] However, investigators have reported deletions or insertions of base stretches of varying length in hypermutating B cells and have concluded that this is a byproduct of the somatic hypermutation machinery within the GC rather than a result of V(D)J recombination in earlier stages of B cell ontogeny. 77,78 Furthermore, it appears that several types of oncogene translocations and Ig HC/LC trancations in heavy chain disease and AL amyloidosis are the result of this phenomenon.…”