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Recurrent disruption of the Iμ splice donor site in t(14;18) positive lymphomas : A potential molecular basis for aberrant downstream class switch recombination
Author(s) -
Ruminy Philippe,
Jardin Fabrice,
Penther Dominique,
Picquenot JeanMichel,
Parmentier Françoise,
Buchonnet Gérard,
Bertrand Philippe,
Tilly Hervé,
Bastard Christian
Publication year - 2007
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20453
Subject(s) - immunoglobulin class switching , biology , allele , genetics , rna splicing , germinal center , gene , exon , germline , locus (genetics) , b cell , antibody , rna
Abstract t(14;18) positive lymphomas are mature germinal center B‐cell neoplasms. In agreement with this cellular origin, most have somatically mutated immunoglobulin variable genes and the IGH@ locus has almost always been reorganized by class switch recombination (CSR). However, contrasting with normal B‐cells, a majority of cases still express an IgM while the constant genes are normally rearranged only on the non‐productive allele. Concurrently, aberrant intra‐allelic junctions involving downstream switch regions, with a lack of engagement of the switch μ (Sμ), often accumulate on the functional alleles, suggesting some recurrent CSR perturbation during the onset of the disease. To clarify these surprising observations, we addressed the accessibility of the Sμ to the CSR machinery in a large series of patients by characterizing the mutations that are expected to accumulate at this place upon CSR activation. Our data indicate that the Sμ is mutated in a large majority of cases, often on both alleles, indicating that these cells usually reach a differentiation stage where CSR is activated and where this region remains accessible. Interestingly, we also identified a significant cluster of mutations at the splicing donor site of the first exon of the Sμ germline transcripts, on the functional allele. This location suggests a possible relation with CSR perturbations in lymphoma and the clustering points to a probable mechanism of selection. In conclusion, our data suggest that an acquired mutation at the splicing donor site of the Sμ transcripts may participate in the selection of lymphoma cells and play a significant role during the onset of the disease. © 2007 Wiley‐Liss, Inc.