title: Evidence for an oncogenic modifier role for mutant histone acetyltransferases in diffuse large B-cell lymphoma.
abstract: Mutations in histone acetyltransferases (HATs) are among the most common mutations in diffuse large B-cell lymphoma (DLBCL). We previously showed that two human DLBCL cell lines, RC-K8 and SUDHL2, express C-terminally truncated, HAT domain-deficient p300 proteins (p300ΔC) that are required for optimal cell proliferation. Microarray analysis of mRNA expression in RC-K8 cells following p300ΔC knockdown shows upregulation of NF-κB and p53 gene expression programs and downregulation of a MYC gene expression program. Experiments indicate that these gene expression changes are due to inhibitory effects of p300ΔC on NF-κB activity and on p53 protein levels and stimulatory effects on MYC protein levels, suggesting that p300ΔC mutants enhance the proliferation of DLBCL cells by adjusting the transcriptional output of cell-specific oncoproteins. We propose that p300/CBP gene truncation represents a new class of oncogenic mutation that optimizes the activity of context-specific oncogenic transcription factors. We propose 'oncogenic modifier' to describe such mutations.
authors.affiliation: a Department of Biology , Boston University , Boston , MA , USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Haery
authors.affiliation: a Department of Biology , Boston University , Boston , MA , USA.
authors.forename: Sultan
authors.initials: S
authors.lastname: Mussakhan
authors.affiliation: a Department of Biology , Boston University , Boston , MA , USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Waxman
authors.affiliation: a Department of Biology , Boston University , Boston , MA , USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Gilmore
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D060045:Genes, Modifier; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009857:Oncogenes; D011485:Protein Binding; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases
keywords: Diffuse large B-cell lymphoma; MYC; NF-κB; histone acetyltransferase; mutation; p300