BCL6: From biochemistry to therapeutic targeting

Abstract

BCL6 is a transcriptional repressor that is required for formation of germinal centers (GC) and consequently for immunoglobulin affinity maturation. During the transit through the GC stage, BCL6 function and expression is highly regulated by signal from T cell and dendritic cells. BCL6 is frequently constitutively expressed in diffuse large B-cell lymphomas (DLBCL) and is thus suspected of being a lymphoma oncogene. BCL6 mediates transcriptional repression by interacting with a number of different corepressors including the SMRT, NCOR and BCOR proteins. We wished to dissect out the contribution of the various corepressors to the transcriptional repression effects of BCL6. We first engineered a BCL6 peptide inhibitor (BPI) that specifically prevents BCL6 from binding to NCOR and SMRT. BPI blocked recruitment of N-COR and SMRT to BCL6 target genes, remodeled the promoter chromatin of these genes to an active state and induced target gene expression. When injected into mice, BPI abrogates GC formation similar to the BCL6 null phenotype. Germinal center formation is thus dependent on BCL6 recruitment of SMRT/NCOR to its target genes. To understand the biological functions of BCL6 we performed ChIP on chip on BCL6 and several of its corepressors. Surprisingly, we found that BCL6 forms distinct transcriptional complexes at different target genes functionally clustered. We observed that CD40 signaling can specifically disrupts those genes in which BCL6 repression is dependent on SMRT and NCOR, similar to the effect of BPI. Therefore T cell signaling through CD40 can rapidly modulate BCL6 target genes expression. Finally, we showed that BCL6 target genes were differentially regulated in the most common subtype of DLCBL---called BCR lymphomas. BCR lymphomas were uniformly killed by BPI, while non-BCR lymphomas were uniformly resistant both in vitro and in vivo. This proved BCL6 to be necessary for the maintenance of the malignancy. Therefore, patients with BCR lymphomas were identified as the best possible candidates for a rational targeted BCL6 inhibition therapy.