Inactivating mutations of acetyltransferase genes in B-cell lymphoma

By L. Pasqualucci, D. Dominguez-Sola, A. Chiarenza, G. Fabbri, A. Grunn, V. Trifonov, L. Kasper, Stephanie L. Lerach, Hongyan Tang, Jing Ma and 8 more. Nature, 2011

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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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/18f466cefd898563c64224dbca7d42407f04b742

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Citations in the corpus

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder (2011, background): “Recent studies showed that they behave as tumor-suppressor genes in various tumor”
Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. (2017, neutral): “1 (https://gdc-api.nci.nih.gov/v0/data/a0bb9765-3f03-485b-839d-7dce4a9bcfeb), using RSEM (Pasqualucci et al., 2011) and normalized within-sample to a fixed upper quartile.”
Histone Modifications and Cancer. (2016, background): “7A of Busslinger and Tarakhovsky 2014), making the resultant cells more tumorigenic via altered pathways that tolerate DNA damage yet evade apoptosis and cell-cycle arrest (Pasqualucci et al. 2011).”
Wnt signaling in cancer. (2012, background): “Mutations in the gene coding for the CREB binding protein (CREBBP/CBP) have been identified in acute lypmhoblastic leukemia and B-cell lymphoma (Mullighan et al. 2011; Pasqualucci et al. 2011).”
Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation (2011, background): “, in DLBCL, where an analogous approach has led to the identification of a few highly recur rent genetic lesions (Pasqualucci et al., 2011).”
Cancer epigenetics: from mechanism to therapy. (2012, background): “…examples of recurrent chromosomal translocations (e.g., MLL-CBP [Wang et al., 2005] and MOZ-TIF2 [Huntly et al., 2004]) or coding mutations (e.g., p300/CBP [Iyer et al., 2004; Pasqualucci et al., 2011]) involving various KATs in a broad range of solid and hematological malignancies (Figure 3).”
Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma (2013, neutral): “7), confirming previous studies 9-12 .”
Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma (2011, background): “and inactivation of the acetyltransferase genes CREBBP and EP300 (ref”