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The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells

Abstract

The human proto-oncogene BCL6 encodes a BTB/POZ-zinc-finger transcriptional repressor that is necessary for germinal-centre formation and is implicated in the pathogenesis of B-cell lymphoma1,2,3. The precise function of BCL6 in germinal-centre development and lymphomagenesis is unclear because very few direct BCL6 target genes have been identified4,5,6,7. Here we report that BCL6 suppresses the expression of the p53 (also known as tp 53) tumour suppressor gene and modulates DNA damage-induced apoptotic responses in germinal-centre B cells. BCL6 represses p53 transcription by binding two specific DNA sites within the p53 promoter region and, accordingly, p53 expression is absent in germinal-centre B cells where BCL6 is highly expressed. Suppression of BCL6 expression via specific short interfering RNA leads to increased levels of p53 messenger RNA and protein both under basal conditions and in response to DNA damage. Most notably, constitutive expression of BCL6 protects B cell lines from apoptosis induced by DNA damage. These results suggest that an important function of BCL6 is to allow germinal-centre B cells to tolerate the physiological DNA breaks required for immunoglobulin class switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response. These findings also imply that deregulated BCL6 expression contributes to lymphomagenesis in part by functional inactivation of p53.

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Figure 1: Transcriptional repression of the p53 promoter by BCL6.
Figure 2: BCL6 binds to the p53 promoter region in vivo.
Figure 3: Suppression of BCL6 by siRNA induces p53 protein and mRNA expression.
Figure 4: Constitutive expression of BCL6 protects from DNA damage-induced apoptosis in B cells.

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Acknowledgements

We thank G. Cattoretti for help with the immunofluorescent staining of human tonsil, U. Klein for RNA samples of normal subset B cells and K. Basso for help with the analysis of p53 and BCL6 expression by microarray. We are grateful to L. Pasqualucci, R. Baer and W. Gu for discussions and for critically reading the manuscript. R.T.P. is supported by a pre-doctoral fellowship in Immunology from the NIH. This work was supported by grants from the National Institute of Health to R.D.-F.

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Correspondence to Riccardo Dalla-Favera.

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Supplementary information

Supplementary Figure 1

Analysis of BCL6 and p53 expression. (PDF 179 kb)

Supplementary Figure 2

Comparative analysis of p53 mutations/deletions and BCL6 rearrangements in DLBCL. (PDF 52 kb)

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Phan, R., Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639 (2004). https://doi.org/10.1038/nature03147

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