Recurrent disruption of the Imu splice donor site in t(14;18) positive lymphomas: a potential molecular basis for aberrant downstream class switch recombination.
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 mu (Smu), 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 Smu 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 Smu 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 Smu 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 Smu transcripts may participate in the selection of lymphoma cells and play a significant role during the onset of the disease.
Ruminy
Philippe
P
Groupe d'Etude des Proliférations Lymphoïdes, Centre Henri Becquerel, INSERM U614, IFR23, 76000 Rouen, France. phirum@rouen.fnclcc.fr
Jardin
Fabrice
F
Penther
Dominique
D
Picquenot
Jean-Michel
JM
Parmentier
Françoise
F
Buchonnet
Gérard
G
Bertrand
Philippe
P
Tilly
Hervé
H
Bastard
Christian
C
D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007134:Immunoglobulin Switch Region; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
D022821:RNA Splice Sites