RESUMEN
The BCL6 gene codes for a zinc-finger transcription factor and is involved in chromosomal rearrangements in 30-40% of diffuse large-cell lymphoma (DLCL). These rearrangements cluster within the 5' regulatory region of BCL6 spanning its first non-coding exon. To determine the functional consequences of these alterations, we have analyzed the structure of the rearranged BCL6 alleles and their corresponding RNA and protein species in two DLCL biopsies and one tumor cell line which carried the t(3;14)(q27;q32) translocation involving the BCL6 and immunoglobulin heavy-chain (IgH) loci. In all three cases, the breakpoints were mapped within the IgH switch region and the BCL6 first intron, leading to the juxtaposition of part of the IgH locus upstream and in the same transcriptional orientation to the BCL6 coding exons. An analysis of cDNA clones showed that these recombinations generate chimeric IgH-BCL6 transcripts which initiated from IgH germline transcript promoters (I mu or I gamma 3), but retain a normal BCL6 coding domain. In the tumor cell line, the chimeric I gamma 3-BCL6 allele, but not the germline BCL6 gene, was transcriptionally active and produced a normal BCL6 protein. These findings indicate that t(3;14) translocations alter BCL6 expression by promoter substitution and imply that the consequence of these alterations is the deregulated expression of a normal BCL6 protein.
Asunto(s)
Proteínas de Unión al ADN/genética , Linfoma de Células B/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Translocación Genética , Alelos , Secuencia de Bases , Quimera/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 3/genética , Clonación Molecular , Cartilla de ADN/genética , ADN Complementario/genética , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Genes de Inmunoglobulinas , Humanos , Linfoma de Células B Grandes Difuso/genética , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas c-bcl-6 , Células Tumorales CultivadasRESUMEN
The molecular pathogenesis of diffuse large-cell lymphoma (DLCL), the most frequent and clinically relevant type of lymphoma, is unknown. A gene was cloned from chromosomal translocations affecting band 3q27, which are common in DLCL. This gene, BCL-6, codes for a 79-kilodalton protein that is homologous with zinc finger-transcription factors. In 33 percent (13 of 39) of DLCL samples, but not in other types of lymphoid malignancies, the BCL-6 gene is truncated within its 5' noncoding sequences, suggesting that its expression is deregulated. Thus, BCL-6 may be a proto-oncogene specifically involved in the pathogenesis of DLCL.