In normal B cells, CBP-mediated acetylation of BCL6 leads to inactivation of its transrepression function, while the same post-translational modification represents an essential requirement for activation of the p53 tumor suppressor functions (left panel). TP53 is also a direct target of BCL6 transcriptional repression in GC B cells, a mechanism that allows the execution of DNA remodeling events such as CSR and SHM, without eliciting DNA damage responses. This fine balance is disrupted in nearly one third of DLBCL, owing to the presence of mutations and/or deletions in CREBBP and, less frequently, EP300 (right panel). Deregulation of the BCL6 oncoprotein and impairment of the p53 tumor suppressor function represent two of presumably many mechanisms by which CREBBP/EP300 genetic lesions contribute to DLBCL transformation.