Title | Inactivating mutations of acetyltransferase genes in B-cell lymphoma. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, Kasper LH, Lerach S, Tang H, Ma J, Rossi D, Chadburn A, Murty VV, Mullighan CG, Gaidano G, Rabadan R, Brindle PK, Dalla-Favera R |
Journal | Nature |
Volume | 471 |
Issue | 7337 |
Pagination | 189-95 |
Date Published | 2011 Mar 10 |
ISSN | 1476-4687 |
Keywords | Acetyl Coenzyme A, Acetylation, Acetyltransferases, Animals, Base Sequence, Cells, Cultured, CREB-Binding Protein, DNA-Binding Proteins, E1A-Associated p300 Protein, Gene Expression Regulation, Neoplastic, HEK293 Cells, Histone Acetyltransferases, Humans, Lymphoma, B-Cell, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Mice, Mutation, Mutation, Missense, Polymorphism, Single Nucleotide, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-6, Recurrence, Sequence Deletion, Tumor Suppressor Protein p53 |
Abstract | 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. |
DOI | 10.1038/nature09730 |
Alternate Journal | Nature |
PubMed ID | 21390126 |
Grant List | U54-AI057158 / AI / NIAID NIH HHS / United States R01-CA37295 / CA / NCI NIH HHS / United States DE018183 / DE / NIDCR NIH HHS / United States P01-CA092625 / CA / NCI NIH HHS / United States 1R01LM010140-01 / LM / NLM NIH HHS / United States |
Related Faculty:
Amy Chadburn, M.D.