Reprogramming specific gene expression pathways in B-cell lymphomas.

The BCL6 transcriptional repressor is normally expressed during the germinal center phase of B-cell differentiation. Germinal center B-cells typically undergo rapid proliferation in spite of accumulating DNA damage caused by class switch recombination and somatic hypermutation. BCL6 is required to license B-cells for the germinal center reaction and its down regulation appears to be important for cells to exit this stage and undergo further differentiation. BCL6 appears to mediate these biological effects by recruiting corepressor complexes to silence critical cell cycle checkpoint and differentiation related genes. Based on our data and recent publications, we propose that these gene pathways are regulated through distinct transcriptional mechanisms, which can be specifically targeted to reprogram B-cells preferentially for either growth suppression and apoptosis, or differentiation. As BCL6 plays a central role in the pathogenesis of diffuse large B-cell lymphoma, we predict that targeting BCL6 transcriptional repression complexes in malignant B-cells may constitute a novel form of transcription therapy for lymphomas and possibly other tumors.