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.

Mutations in the gene encoding the KMT2D (also called MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of KMT2D mutations and their role in lymphomagenesis are unknown. Here we show that FL/DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B-cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B-cells and enhances B cell proliferation in mice. In mice overexpressing BCL2, which develop GC-derived lymphomas resembling human tumors, genetic ablation of Kmt2d leads to a further increase in tumor incidence. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may represent a rational therapeutic approach for targeting early tumorigenic events.

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