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A peptide aptamer to antagonize BCL-6 function

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Abstract

BCL-6 is a transcription factor essential for germinal centre B-cell development. The BCL-6 gene is involved in diffuse large-cell lymphoma and overexpressed in other types of non-Hodgkin's lymphoma and in high-grade breast cancer. BCL-6 is a transcriptional repressor whose N-terminal POZ domain mediates protein–protein interactions to exert its effects. Reasoning that disruption of POZ domain-mediated interactions may be an effective route to antagonizing the effects of BCL-6 in lymphoma, we screened a library for peptide aptamers that specifically bind to BCL-6 POZ and not the POZ domains of related proteins and describe here the first of these reagents, Apt48. Apt48 binds BCL-6 POZ in a manner distinct from the transcriptional corepressor SMRT, yet was found to prevent BCL-6-mediated repression of a luciferase reporter gene. Apt48 also reproduced several previously validated effects of BCL-6 inhibition. Notably, expression of the differentiation markers CD69, Blimp-1 and cyclin D2 was increased in B-cell lines when Apt48 was expressed. We also show that expression of Apt48 restores cytokine-mediated growth arrest to BCL-6 overexpressing cells. Thus, we have identified a peptide aptamer that affects a function of BCL-6 that is required to prevent differentiation of proliferating B cells.

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Acknowledgements

We thank Dr Yusuke Murakami (Wellcome Trust Immunology Unit, Cambridge) for help with cell culture conditions, and Sue Penryn-Lowe (MRC Cancer Cell Unit, Hutchison/MRC Research Centre) for her help both with cell counting and with microscopy and imaging. This work was funded by a grant from the Development Committee of Cancer Research UK (to SDW). Work in the PKF lab is funded by a Grant-in-Aid from the Medical Research Council to the Cancer Cell Unit. SAT acknowledges the receipt of an MRC Studentship.

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Authors and Affiliations

  1. MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK

    A Chattopadhyay, S A Tate & P Ko Ferrigno

  2. University of Cambridge/Cancer Research UK Department of Oncology, Hutchison/MRC Research Centre, Cambridge, UK

    S A Tate & P Ko Ferrigno

  3. Department of Haematology, Division of Investigative Sciences, Imperial College London, Hammersmith Hospital, London, UK

    A Chattopadhyay, R W Beswick & S D Wagner

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  1. A Chattopadhyay
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  2. S A Tate
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  3. R W Beswick
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  4. S D Wagner
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  5. P Ko Ferrigno
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Correspondence to S D Wagner or P Ko Ferrigno.

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Chattopadhyay, A., Tate, S., Beswick, R. et al. A peptide aptamer to antagonize BCL-6 function. Oncogene 25, 2223–2233 (2006). https://doi.org/10.1038/sj.onc.1209252

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  • DOI: https://doi.org/10.1038/sj.onc.1209252

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