B cell receptor engagement and T cell contact induce Bcl-6 somatic hypermutation in human B cells: identity with Ig hypermutation.
The human bcl-6 proto-oncogene has been found to be mutated in both neoplastic and normal B cells. We used CL-01 cells, our monoclonal model of germinal center differentiation, and normal human B cells to explore the induction requirements and the modalities of bcl-6 hypermutation. As we have previously shown, CL-01 cells are IgM+ IgD+ and effectively mutate the expressed Ig VHDJH and V lambda J lambda genes and switch to IgG, IgA, and IgE upon B cell receptor engagement and contact with CD4+ T cells through CD40:CD154 and CD80:CD28 coengagement. In this paper we showed that the same stimuli induce somatic hypermutation of bcl-6 in CL-01 and normal IgM+ IgD+ B cells. bcl-6 hypermutation was not accompanied by translocation of this proto-oncogene or hypermutation of the beta-actin gene, and it did mimic Ig hypermutation. It was associated with transcription initiation, in that it targeted the first exon and a 696-bp sequence immediately downstream (approximately 0.6 kb) of the transcription initiation site while sparing further downstream (approximately 2.5 kb) and upstream (approximately 0.1 kb) areas. bcl-6 hypermutation displayed an overall rate of 2.2 x 10-4 changes/base/cell division with characteristic nucleotide preferences and showed strand polarity. These findings show that B cell receptor engagement promotes hypermutation in genes other than Ig, and suggest that cis-regulating elements similar to those of the Ig locus exist in bcl-6.
Zan
H
H
Division of Molecular Immunology, Department of Pathology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Li
Z
Z
Yamaji
K
K
Dramitinos
P
P
Cerutti
A
A
Casali
P
P
D020816:Amino Acid Motifs / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D001482:Base Composition; D001483:Base Sequence; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand; D002450:Cell Communication / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics*; D015226:Dinucleoside Phosphates / Q000235:genetics; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D006801:Humans; D007072:Immunoglobulin D / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000276:immunology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000276:immunology; D014178:Translocation, Genetic / Q000276:immunology
D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D008024:Ligands; C000715470:MAS1 protein, human; D008562:Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors; D023201:CD40 Ligand