Inactivating mutations of acetyltransferase genes in B-cell lymphoma

B-cell non-Hodgkin lymphoma (B-NHL) comprises biologically and clinically distinct diseases whose pathogenesis is associated with genetic lesions affecting oncogenes and tumor-suppressor genes. We report here that the two most common types, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), harbor frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. Overall, ~39% of DLBCL and 41% of FL cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions commonly affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 onco-protein and activation of the p53 tumor-suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-NHL, and have direct implications for the use of drugs targeting acetylation/deacetylation mechanisms.