title: Somatic mutation of bcl-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia.
abstract: Somatic mutation in immunoglobulin variable (V) region genes occurs largely in the germinal center and, after neoplastic transformation, imprints V genes of B-cell tumors with the mutational history of the cell of origin. Recently, it has been found that chronic lymphocytic leukemia (CLL) consists of 2 subsets, each with a different clinical course, one with unmutated V(H) genes consistent with a naive B cell, and the other with mutated V(H) genes consistent with transit through the germinal center. However, somatic mutation also occurs at another distinct locus, the 5' noncoding region of the bcl-6 gene, in both B-cell tumors and in normal germinal center B cells. To probe the suggestive link between the occurrence of mutations in V(H) and bcl-6 genes, we analyzed the nature of somatic mutation at these distinct loci in the 2 CLL subsets. Unexpectedly, we found no such link in the CLLs defined by unmutated V(H) genes, with 4 of 10 cases clearly showing mutations in bcl-6. In those CLLs defined by somatically mutated V(H) genes, 4 of 9 cases predictively showed bcl-6 mutations. The frequency of bcl-6 mutations was comparable in both subsets, with mutations being biallelic, and in 3 of 8 cases indicative of clonal origins. Surprisingly, intraclonal variation, which is not a feature of V(H) genes in CLL, was found in 6 of 8 cases in both subsets. These data indicate that somatic mutation of the V(H) and bcl-6 loci may not necessarily occur in tandem in CLL, suggesting diverse pathways operating on the 2 genes.
authors.affiliation: Molecular Immunology Group, Tenovus Laboratory, Southampton University Hospitals, Southampton, UK. sss1@soton.ac.uk
authors.forename: S S
authors.initials: SS
authors.lastname: Sahota
authors.forename: Z
authors.initials: Z
authors.lastname: Davis
authors.forename: T J
authors.initials: TJ
authors.lastname: Hamblin
authors.forename: F K
authors.initials: FK
authors.lastname: Stevenson
mesh_terms: D002872:Chromosome Deletion; D003001:Cloning, Molecular; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005803:Genes, Immunoglobulin; D005914:Globins / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007438:Introns; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D005914:Globins