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Somatic mutations of the BCL‐6 gene and B‐cell lymphoma oncogenesis Volume 10, issue 1, Janvier-Février 2004

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Département d‘hématologie clinique, centre Henri Becquerel, Rouen, France Laboratoire de génétique oncologique et Emi 9906‐IRFMP n° 23, centre Henri Becquerel, Rouen, France

The BCL‐6 gene, located on chromosome 3q27, encodes for a transcritptional repressor implicated in germinal center (GC) formation, B and T cell maturation, apoptosis, cell cycle control and senescence. BCL‐6 is targeted in lymphoma by numerous structural changes including translocations involving various partners chromosomes, deletions of the 5‘ part of the gene and somatic mutations (SM). SM lie in the proximity of the BCL‐6 promoter, within the 5‘ part of the first intron, and cluster within a 1 Kb region. SM are observed in 30% of normal centrocytes and centroblastes but not in naive or pregerminal center B‐cells. As observed in immunoglobulin variable genes (IgV), BCL‐6 SM are mainly biallelic, single nucleotide substitutions with a preference for transition over transversion, and rarely short deletions or additions. In vitro, SM are initiated by BCL‐6 gene transcription and during B‐cell receptor engagement, contact with CD4+ cells via the CD40\CD154 and CD80\CD28 co‐stimulatory pathways. BCL‐6 SM are observed in 70% of diffuse large B‐cells lymphomas, 30% of follicular lymphomas and at various frequencies in all lymphoma subtypes derived from GC B‐cells. Accumulation of SM during higher grade transformation of follicular lymphoma, recurrent mutations and a mutation clustering effect suggest that part of the mutations may be selected by their effect on the survival of tumoral clones. SM may target regulatory regions located within the first exon and the 5‘ portion of the first intron, leading to the deregulation of BCL‐6 gene expression. Prognosis value of BCL‐6 mutations in lymphoma is unknown and seems less prominent than the well‐established IgV SM prognosis value in chronic lymphocytic leukaemia. Furthermore, SM process and chromosomal translocation may be related as suggested by the overlap between the breakpoint cluster region and the mutation domain. In addition to IgV and BCL‐6, The SM process appears to misfire multiple genes in normal GC B‐cells (CD95, CD79) and in lymphoma cells (PAX‐5, c‐MYC, PIM‐1 et RhOH\TTF), indicating that an aberrant hypermutation process may represent a major contributor to lymphomagenesis.