Inactivating mutations of acetyltransferase genes in B-cell lymphoma.
Inactivating mutations of acetyltransferase genes in B-cell lymphoma.
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DOI：
10.1038/nature09730
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发表时间：
2011-03-10
期刊：
影响因子：
64.8
通讯作者：
Dalla-Favera, Riccardo
中科院分区：
文献类型：
--
作者：
Pasqualucci, Laura;Dominguez-Sola, David;Chiarenza, Annalisa;Fabbri, Giulia;Grunn, Adina;Trifonov, Vladimir;Kasper, Lawryn H.;Lerach, Stephanie;Tang, Hongyan;Ma, Jing;Rossi, Davide;Chadburn, Amy;Murty, Vundavalli V.;Mullighan, Charles G.;Gaidano, Gianluca;Rabadan, Raul;Brindle, Paul K.;Dalla-Favera, Riccardo
b细胞非霍奇金淋巴瘤（B-NHL）包括生物学和临床不同的疾病，其发病机制与影响癌基因和肿瘤抑制基因的遗传病变有关。我们在这里报道了两种最常见的类型，滤泡性淋巴瘤（FL）和弥漫性大b细胞淋巴瘤（DLBCL），它们具有频繁的结构改变，使CREBBP失活，更罕见的是，EP300失活，EP300是两种高度相关的组蛋白和非组蛋白乙酰转移酶（HATs），在多种信号通路中充当转录共激活因子。总体而言，约39%的DLBCL和41%的FL病例表现出基因组缺失和/或体细胞突变，这些突变会去除或使这两个基因的HAT编码域失活。这些病变通常影响一个等位基因，表明减少HAT剂量对淋巴瘤发生很重要。我们证明了乙酰化介导的BCL6癌蛋白失活和p53肿瘤抑制因子激活的特异性缺陷。这些结果确定CREBBP/EP300突变是常见形式B-NHL共有的主要发病机制，并对靶向乙酰化/去乙酰化机制的药物使用具有直接意义。
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.
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