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,
*
Division of Molecular Immunology, Department of Pathology,
Department of Microbiology and Immunology, Weill Medical College of Cornell University, and
The Immunology Program, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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
J 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 ß-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 (
0.6 kb) of the transcription initiation site while
sparing further downstream (2.5 kb) and upstream (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.
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