BCL6 mediates lymphomagenesis through 2 distinct pathways. Our data suggest a model where recruitment of SMRT, N-CoR, and BCoR through the BCL6 BTB domain mediates repression of ATR, TP53, and CDKN1A, which facilitates survival and proliferation. This allows activated B cells to acquire the CB phenotype and is required for survival of DLBCL. On the other hand, recruitment of the MTA3 protein through the RD2 mediates repression of PRDM1 and hence blocks differentiation, preventing B cells from exiting the GC and contributing to lymphomagenesis. The ETO corepressor and class II HDACs bind to the zinc finger region of BCL6, but their functions are unknown. Combined blockade of the BTB and RD2 biochemical mechanisms of action of BCL6 results in more profound disruption of the BCL6 oncogenic transcriptional program and enhanced DLBCL cell death.