Journal Article

Inactivating mutations of acetyltransferase genes in B-cell lymphoma

Chiarenza, Annalisa, Mullighan, Charles G., Chadburn, Amy, Lerach, Stephanie, Pasqualucci, Laura, Fabbri, Giulia, Murty, Vundavalli V., Gaidano, Gianluca, Trifonov, Vladimir, Rossi, Davide, Brindle, Paul K., Dalla-Favera, Riccardo, Ma, Jing, Kasper, Lawryn H., Dominguez-Sola, David, Rabadan, Raul, Grunn, Adina, Tang, Hongyan

2011

Overview

B-cell non-Hodgkin’s lymphoma comprises biologically and clinically distinct diseases the pathogenesis of which is associated with genetic lesions affecting oncogenes and tumour-suppressor genes. We report here that the two most common types—follicular lymphoma and diffuse large B-cell lymphoma—harbour 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 signalling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions usually affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumour suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-cell non-Hodgkin’s lymphoma, with direct implications for the use of drugs targeting acetylation/deacetylation mechanisms. CREBBP and EP300 mutations in B-cell lymphoma In three different subtypes of B-cell lymphomas, two papers report frequent somatic mutations in the genes CREBBP and EP300 , which are present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations disrupt these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to anticancer drugs. These studies may provide a rationale for the use of histone deacetylase inhibitors in certain B-cell lymphomas. In three different subtypes of B-cell lymphomas, two papers now report frequent somatic mutations in CREBBP and EP300 , present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations found inactivate these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to therapeutic drugs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420/2489/68 / 692/699/67/1990/291/1621/1915 / Abnormalities / Acetyl Coenzyme A - metabolism / Acetylation / Acetyltransferases - chemistry / Acetyltransferases - deficiency / Acetyltransferases - genetics / Acetyltransferases - metabolism / Animals / B cells / Base Sequence / Binding sites / Biological and medical sciences / Cell cycle / Cells, Cultured / Congenital diseases / CREB-Binding Protein - chemistry / CREB-Binding Protein - deficiency / CREB-Binding Protein - genetics / CREB-Binding Protein - metabolism / DNA-Binding Proteins - metabolism / E1A-Associated p300 Protein - chemistry / E1A-Associated p300 Protein - deficiency / E1A-Associated p300 Protein - genetics / E1A-Associated p300 Protein - metabolism / Gene Expression Regulation, Neoplastic / Gene mutations / Genes / Genetic aspects / Genetic engineering / Genomes / Health aspects / HEK293 Cells / Hematologic and hematopoietic diseases / Histone Acetyltransferases - chemistry / Histone Acetyltransferases - deficiency / Histone Acetyltransferases - genetics / Histone Acetyltransferases - metabolism / Humanities and Social Sciences / Humans / Inactivation / Lesions / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Lymphoma / Lymphoma, B-Cell - enzymology / Lymphoma, B-Cell - genetics / Lymphoma, B-Cell - pathology / Lymphoma, Follicular - enzymology / Lymphoma, Follicular - genetics / Lymphoma, Follicular - pathology / Lymphoma, Large B-Cell, Diffuse - enzymology / Lymphoma, Large B-Cell, Diffuse - genetics / Lymphoma, Large B-Cell, Diffuse - pathology / Lymphomas / Medical sciences / Mice / multidisciplinary / Mutation / Mutation - genetics / Mutation, Missense - genetics / Pathogenesis / Polymorphism, Single Nucleotide - genetics / Protein Binding / Protein Structure, Tertiary - genetics / Proteins / Proto-Oncogene Proteins c-bcl-6 / Recurrence / Science / Science (multidisciplinary) / Sequence Deletion - genetics / Tumor Suppressor Protein p53 - metabolism