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Inactivating mutations of acetyltransferase genes in B-cell lymphoma.

Nature | Mar 10, 2011

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.

Pubmed ID: 21390126 RIS Download

Mesh terms: Acetyl Coenzyme A | Acetylation | Acetyltransferases | Animals | Base Sequence | CREB-Binding Protein | Cells, Cultured | DNA-Binding Proteins | E1A-Associated p300 Protein | Gene Expression Regulation, Neoplastic | HEK293 Cells | Histone Acetyltransferases | Humans | Lymphoma, B-Cell | Lymphoma, Follicular | Lymphoma, Large B-Cell, Diffuse | Mice | Mutation | Mutation, Missense | Polymorphism, Single Nucleotide | Protein Binding | Protein Structure, Tertiary | Proto-Oncogene Proteins c-bcl-6 | Recurrence | Sequence Deletion | Tumor Suppressor Protein p53

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Associated grants

  • Agency: NIAID NIH HHS, Id: U54-AI057158
  • Agency: NCI NIH HHS, Id: R01-CA37295
  • Agency: NIDCR NIH HHS, Id: DE018183
  • Agency: NCI NIH HHS, Id: R37 CA037295-28
  • Agency: NCI NIH HHS, Id: R01 CA037295
  • Agency: NCI NIH HHS, Id: R37 CA037295
  • Agency: NCI NIH HHS, Id: P01 CA092625
  • Agency: NIDCR NIH HHS, Id: R21 DE018183
  • Agency: NCI NIH HHS, Id: P30 CA021765
  • Agency: NIAID NIH HHS, Id: U54 AI057158
  • Agency: NCI NIH HHS, Id: P01-CA092625
  • Agency: NLM NIH HHS, Id: 1R01LM010140-01
  • Agency: NLM NIH HHS, Id: R01 LM010140
  • Agency: NCI NIH HHS, Id: P01 CA092625-05

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