Inactivating mutations of acetyltransferase genes in B-cell lymphoma

Laura Pasqualucci (), David Dominguez-Sola, Annalisa Chiarenza, Giulia Fabbri, Adina Grunn, Vladimir Trifonov, Lawryn H. Kasper, Stephanie Lerach, Hongyan Tang, Jing Ma, Davide Rossi, Amy Chadburn, Vundavalli V. Murty, Charles G. Mullighan, Gianluca Gaidano, Raul Rabadan, Paul K. Brindle and Riccardo Dalla-Favera ()
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Laura Pasqualucci: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
David Dominguez-Sola: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
Annalisa Chiarenza: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
Giulia Fabbri: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
Adina Grunn: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
Vladimir Trifonov: Columbia University
Lawryn H. Kasper: St Jude Children’s Research Hospital
Stephanie Lerach: St Jude Children’s Research Hospital
Hongyan Tang: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
Jing Ma: The Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital
Davide Rossi: Amedeo Avogadro University of Eastern Piedmont
Amy Chadburn: Northwestern University, Feinberg School of Medicine
Vundavalli V. Murty: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
Charles G. Mullighan: St Jude Children’s Research Hospital
Gianluca Gaidano: Amedeo Avogadro University of Eastern Piedmont
Raul Rabadan: Columbia University
Paul K. Brindle: St Jude Children’s Research Hospital
Riccardo Dalla-Favera: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University

Nature, 2011, vol. 471, issue 7337, 189-195

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09730

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