Targeted somatic mutation of the BCL6 proto-oncogene and its impact on lymphomagenesis.
Cloning translocation breakpoints which cluster suspiciously to specific chromosomal loci has proved fruitful, leading to the identification of genes implicated in the onset of hematological malignancy. One of the most notable is BCL6, located on chromosome 3q27. The BCL6 is now known to encode a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation and survival. Unusually, the BCL6 gene locus is also actively targeted by the somatic mutation (SM) mechanism, at a rate indicative of specific, regulated events in both normal and malignant B-cells. These mutations occur in approximately 30% of normal centrocytes and centroblasts, but not in naive or pre-GC B-cells. They are also observed in approximately 70% of diffuse large B-cells lymphomas, approximately 30% of follicular lymphomas (FL) and at various frequencies in many lymphoma subtypes. Mutations are generated in the 5' proximity of the BCL6 promoter, including the first intron and are mainly single nucleotide substitutions, but with insertions and deletions also observed. Mutations in BCL6 occur independently of translocations, although mutational levels can be dramatically influenced by aberrantly translocated chromosomal elements, which map in the vicinity of the gene. Indeed, SMs are directly implicated in the generation of chromosomal translocations, as suggested by the overlap of the breakpoint cluster region and the mutational cluster domain. The prognostic value of the overall level of BCL6 mutations in specific lymphoma populations is, in the main, not as yet fully resolved. The accumulation of mutations in BCL6 during high grade transformation of FL, a mutational clustering and specific recurrent mutations suggest that some mutations may be selected for by their effect on the survival of the tumoral clone. In fact, it is now clear that SM can target and disrupt regulatory motifs in BCL6 to result in upregulated gene expression. Exogenous factors can also perturbate SM in BCL6. Viral infection elevates BCL6 mutational activity, suggesting a potential link with onset of virus-associated lymphoma. These findings to date reveal several mechanisms which can influence specific mutations targeting BCL6, and which may contribute to lymphomagenesis by dysregulating control of BCL6 expression.
Jardin
Fabrice
F
Département d'Hématologie Clinique and Groupe d'étude des proliférations lymphoïdes, Centre Henri Becquerel, Rouen, France. fabrice.jardin@rouen.fnclcc.fr
Sahota
Surinder S
SS
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors