The expanding role of the BCL6 oncoprotein as a cancer therapeutic target

Abstract

BCL6 was initially discovered as an oncogene in B-cell lymphomas, where it drives the malignant phenotype by repressing proliferation and DNA damage checkpoints and blocking B-cell terminal differentiation. BCL6 mediates its effects by binding to hundreds of target genes and then repressing these genes by recruiting several different chromatin-modifying corepressor complexes. Structural characterization of BCL6-corepressor complexes suggested that BCL6 might be a druggable target. Accordingly, a number of compounds have been designed to bind to BCL6 and block corepressor recruitment. These compounds, based on peptide or small-molecule scaffolds, can potently block BCL6 repression of target genes and kill lymphoma cells. In the case of diffuse large B-cell lymphomas (DLBCL), BCL6 inhibitors are equally effective in suppressing both the germinal center B-cell (GCB)- and the more aggressive activated B-cell (ABC)-DLBCL subtypes, both of which require BCL6 to maintain their survival. In addition, BCL6 is implicated in an expanding scope of hematologic and solid tumors. These include, but are not limited to, B- acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer. BCL6 inhibitors have been shown to exert potent effects against these tumor types. Moreover, mechanism-based combinations of BCL6 inhibitors with other agents have yielded synergistic and often quite dramatic activity. Hence, there is a compelling case to accelerate the development of BCL6-targeted therapies for translation to the clinical setting.