TY - JOUR
T1 - Inactivating mutations of acetyltransferase genes in B-cell lymphoma
AU - Pasqualucci, Laura
AU - Dominguez-Sola, David
AU - Chiarenza, Annalisa
AU - Fabbri, Giulia
AU - Grunn, Adina
AU - Trifonov, Vladimir
AU - Kasper, Lawryn H.
AU - Lerach, Stephanie
AU - Tang, Hongyan
AU - Ma, Jing
AU - Rossi, Davide
AU - Chadburn, Amy
AU - Murty, Vundavalli V.
AU - Mullighan, Charles G.
AU - Gaidano, Gianluca
AU - Rabadan, Raul
AU - Brindle, Paul K.
AU - Dalla-Favera, Riccardo
PY - 2011/3/10
Y1 - 2011/3/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952430906&partnerID=8YFLogxK
U2 - 10.1038/nature09730
DO - 10.1038/nature09730
M3 - Article
SN - 0028-0836
VL - 471
SP - 189
EP - 196
JO - Nature
JF - Nature
IS - 7337
ER -