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Inactivating mutations of acetyltransferase genes in B-cell lymphoma

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.

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Figure 1: The CREBBP gene is mutated in DLBCL.
Figure 2: Mutations and deletions of CREBBP are predominantly monoallelic.
Figure 3: CREBBP and EP300 expression in normal and transformed B-cells.
Figure 4: CREBBP missense mutations impair its ability to acetylate BCL6 and p53.
Figure 5: DLBCL-associated mutations in the CREBBP HAT domain decrease its affinity for acetyl-CoA.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

Data deposits

The Affymetrix expression data reported in this paper have been deposited in the NCBI Gene Expression Omnibus (GEO) database (Series Accession Number GSE12195). The SNP Array 6.0 data and the whole exome sequencing data from the seven DLBCL cases have been deposited in dbGaP under accession number phs000328.v1.p1.

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Acknowledgements

We thank Q. Shen and the Molecular Pathology Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University for histology service; W. Gu for discussions and reagents; Y. Tang, M. Li and D. Chao for suggestions; V. Bardwell for the Bcl6 reporter construct; and R. S. K. Chaganti for sharing unpublished information. Whole-exome capture and sequencing were conducted at Roche NimbleGen and 454 Life Sciences. Automated DNA sequencing was performed at Genewiz Inc. This work was supported by NIH grants PO1-CA092625 and RO1-CA37295 (to R.D.-F.), a Specialized Center of Research grant from the Leukemia and Lymphoma Society (to R.D.-F.), NIH grant DE018183, a Cancer Center (CORE) support grant P30 CA021765, and the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital (to P.K.B.), the Northeast Biodefence Center (U54-AI057158) and the National Library of Medicine (1R01LM010140-01) (to R.R.), and the AIRC Special Program Molecular Clinical Oncology—5 per mille (contract number 10007, Milan) (to G.G.). A. Chiarenza is on leave from the Division of Hematology, Ospedale Ferrarotto, University of Catania, Catania, Italy. L.P. is on leave from the University of Perugia Medical School, Perugia, Italy.

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Authors

Contributions

L.P. and R.D.-F. designed the study and wrote the manuscript, with contributions from all authors. L.P. designed and conducted experiments, analysed data and coordinated the study. D.D.-S. designed and conducted experiments, and analysed immunohistochemistry data. A. Chiarenza, G.F. and A.G. conducted CREBBP/EP300 amplification and sequencing analysis. L.H.K., S.L. and P.K.B. were responsible for the experiments in MEF cells. H.T. performed immunohistochemistry and immunofluorescence staining of human tissue biopsies. V.V.M. developed FISH assays and analysed cytogenetic data. C.G.M. and J.M. analysed microarray data. A. Chadburn, D.R. and G.G. provided well-characterized patient samples. V.T. and R.R. developed algorithms and analysed high-throughput sequencing data.

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Correspondence to Laura Pasqualucci or Riccardo Dalla-Favera.

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Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011). https://doi.org/10.1038/nature09730

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