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STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

Oncogene volume 26, pages 224–233 (2007)Cite this article

Abstract

Deregulated expression of BCL6 is a pathogenic event in many lymphomas. BCL6 blocks cellular differentiation by repressing transcription of its target genes, and this may promote tumorigenesis. Conversely, the transcription factor signal transducers and activators of transcription (STAT)5 promotes differentiation in many systems. STAT5 upregulates a number of genes repressed by BCL6, raising the possibility that STAT5 and BCL6 have opposing roles in transcriptional regulation. Therefore, we sought to determine the effects of STAT5 activation on BCL6 expression and function. We found that activation of STAT5 downregulates BCL6 expression in B-lymphoma cells and other hematopoietic cell lines. We identified two potential STAT-binding regions in the first exon and first intron of BCL6 that fell within regions of high inter-species homology, suggesting conservation of regulatory function. STAT5 can bind inducibly and regulate transcription at one of these regions, identifying BCL6 as a STAT5 target gene. Additionally, STAT5-mediated downregulation of BCL6 results in loss of BCL6 repression of its target genes, confirming that STAT5 is a negative regulator of BCL6 function. The STAT5 responsive region of the BCL6 gene is mutated frequently in B-cell lymphomas, suggesting that loss of the repressive effects of STAT5 on BCL6 might contribute to the pathogenesis of these cancers.

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Acknowledgements

This work was supported by the Brent Leahey Fund and the Friends of the Dana-Farber Cancer Institute.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA

    S R Walker, E A Nelson & D A Frank

  2. Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA

    S R Walker, E A Nelson & D A Frank

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  1. S R Walker
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Correspondence to D A Frank.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Walker, S., Nelson, E. & Frank, D. STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26, 224–233 (2007). https://doi.org/10.1038/sj.onc.1209775

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