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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.

B Cell Receptor Engagement and T Cell Contact Induce bcl-6 Somatic Hypermutation in Human B Cells: Identity with Ig Hypermutation