Targeted epigenetic repression of a lymphoma oncogene by sequence-specific histone modifiers induces apoptosis in DLBCL

Abstract

Alterations to the epigenetic landscape of diffuse large B-cell lymphoma (DLBCL) play a fundamental role in deregulating genes involved in normal lymphocyte differentiation. To determine whether targeted epigenetic therapy could reverse these pathogenic chromatin changes and suppress the expression of a lymphoma oncogene, we focused on BCL6, a transcriptional repressor whose aberrant expression is tightly linked to DLBCL proliferation and survival. We fused zinc-finger (ZF) domains specific for regulatory regions in the BCL6 locus to a repressive epigenetic modifier, the Kruppel-associated box (KRAB) repressor domain. Distinct ZF–KRAB fusions repressed the local chromatin landscape, suppressed BCL6 expression, significantly impaired DLBCL growth, and caused widespread cell death in a BCL6-dependent manner. Importantly, expression of ectopic BCL6 protein rescued ZF–KRAB-induced cell death, demonstrating the modifiers’ specificity. We show that sequence-specific epigenetic modifiers can alter oncogene expression and induce apoptosis in cancer cells, underscoring their potential for future development as targeted epigenetic protein therapies.

Keywords:

• Chemotherapeutic approaches
• lymphoma and Hodgkin disease
• transcription factor changes

Acknowledgements

We thank B. Sleckman and O. Koues for helpful comments on the experiments and manuscript.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.1080/10428194.2016.1190973.

Funding information

This work was supported by National Institute of Health grants [CA156690] and [CA188286] (J.E.P. and E.M.O.), [TR000448] (WU-ICTS), and [CA91842] (Siteman Cancer Center).