BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci.
The molecular mechanism involved in the process of antigen-driven somatic hypermutation of Ig genes is unknown, but it is commonly believed that this mechanism is restricted to the Ig loci. B cell lymphomas commonly display multiple somatic mutations clustering in the 5'-regulatory region of BCL-6, a proto-oncogene encoding for a POZ/Zinc finger transcriptional repressor expressed in germinal center (GC) B cells and required for GC formation. To determine whether BCL-6 mutations represent a tumor-associated phenomenon or reflect a physiologic mechanism, we screened single human tonsillar GC B cells for mutations occurring in the BCL-6 5'-noncoding region and in the Ig variable heavy chain sequences. Thirty percent of GC B cells, but not naive B cells, displayed mutations in the 742 bp region analyzed within the first intron of BCL-6 (overall frequency: 5 x 10(-4)/bp). Accordingly, an expanded survey in lymphoid malignancies showed that BCL-6 mutations are restricted to B cell tumors displaying GC or post-GC phenotype and carrying mutated Ig variable heavy chain sequences. These results indicate that the somatic hypermutation mechanism active in GC B cells physiologically targets non-Ig sequences.
Pasqualucci
L
L
Departments of Pathology and Genetics and Development, Columbia University, New York, NY 10032, USA.
Migliazza
A
A
Fracchiolla
N
N
William
C
C
Neri
A
A
Baldini
L
L
Chaganti
R S
RS
Klein
U
U
Küppers
R
R
Rajewsky
K
K
Dalla-Favera
R
R
D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics*; D005803:Genes, Immunoglobulin; D018858:Germinal Center / Q000166:cytology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors