1. ¹MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK
2. ²University of Cambridge/Cancer Research UK Department of Oncology, Hutchison/MRC Research Centre, Cambridge, UK
3. ³Department of Haematology, Division of Investigative Sciences, Imperial College London, Hammersmith Hospital, London, UK

Correspondence: Dr SD Wagner, Department of Haematology, Division of Investigative Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail: simon.wagner@imperial.ac.uk; Dr PK Ferrigno, Department of Oncology, University of Cambridge/Cancer Research UK, Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 2XZ, UK. E-mail: pkf@hutchison-mrc.cam.ac.uk

Received 26 August 2005; Revised 6 October 2005; Accepted 13 October 2005; Published online 5 December 2005.

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.