Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis

• BCL6 maintains a delicate balance between survival and apoptosis in germinal center (GC) B cells.
• BCL6 maintains promoters and enhancers in a poised state in GC and lymphoma cells.
• BCL6 mechanism of action varies among cell types in the immune system.
• BCL6 mechanism-specific targeting kills lymphomas without harming other tissues.

The B cell lymphoma 6 (BCL6) transcriptional repressor is a master regulator of the germinal center (GC) B cell program, required for their unique proliferative and stress tolerant phenotype. Most B cell lymphomas arise from GC B cells and are dependent on the continued or deregulated expression of BCL6 to maintain their survival. The actions of BCL6 in B cells involve formation of distinct chromatin modifying complexes that silence specific promoter and enhancer networks, respectively. The same biochemical mechanisms are maintained in malignant lymphoma cells. Targeted inhibition of these BCL6 functions has emerged as the basis for rational design of lymphoma therapies and combinatorial regimens. In this review, we summarize recent advances on BCL6 mechanisms of action and the deregulation of its target gene networks in lymphoma.