The role of BCL6 in germinal center B cell development and lymphomagenesis.

RANUNCOLO, SM; MELNICK, AM

Manhattan, New York.

Encuentro; Night for the Hematology Fellows.; 2005

Society for the Study of Blood (SSB).

The BCL6 (B-Cell-Lymphoma-6) transcriptional repressor plays a critical role in B-cell physiology, as it is required for establishment of germinal centers and immunoglobulin affinity maturation. BCL6 is also one of the most commonly involved oncogenes in B-cell lymphomas. The reason why BCL6 is required to establish germinal centers is poorly understood. Our data suggest that this activity of BCL6 is tightly linked with its effects in lymphomagenesis. Accordingly, a cell permeable peptide that we designed to specifically block BCL6-mediated transcriptional repression, abrogates germinal center formation in vivo and induces apoptosis and G1-cell cycle arrest in Bcl-6 B-cell lymphoma cell lines. We identified the entire cohort of direct BCL6 target genes in lymphoma cells by performing expression arrays and ChIP on chip. Many of these are central players in DNA damage sensing and apoptosis checkpoints. Based on these and other results, we hypothesize that the specific mechanism of action of BCL6 in both licensing germinal center formation and survival of lymphomas, is to mediate a state of ?tolerance? to DNA damage. We propose that BCL6 achieves this effect by directly repressing expression of three main checkpoint genes, p53, p21 and Chk1. This would allow affinity maturation to occur in normal B-cells, but also results in lymphomagenesis by mediating genomic instability and evasion of apoptosis in response to aberrant mutagenesis. Finally, we predict that overcoming BCL6 mediated transcriptional repression by either shRNA or BPI, will sensitize lymphoma cells to cytotoxic chemotherapy drugs and is thus likely to be an effective strategy to treat patients with B-cell lymphomas. Our preliminary gain and loss of function studies show that BCL6 induces tolerance to DNA damage by blocking DNA damage sensing, and that loss of BCL6 in B-cell lymphomas, sensitizes B-cells to DNA damaging agents. Therefore, we expect our studies to reveal the mechanism by which BCL6 licenses B-cells to undergo affinity maturation, the mechanism of BCL6-mediated lymphomagenesis, and the potential for using our BCL6 blocking agents in the clinical setting to sensitize lymphomas to chemotherapy and radiation.