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.

Keywords:

• Diffuse large B-cell lymphoma
• histone acetyltransferase
• mutation
• MYC
• NF-κB
• p300

Acknowledgements

We thank Adam Gower (Boston University School of Medicine, Microarray and Sequencing Resource Core Facility) and Eduard Drizik (Boston University Clinical and Translational Science Institute (CTSA)) for help with the microarray analysis.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2016.1160083.

This study was supported by the National Institutes of Health [U54-TR001012; CA49248 (to D.J.W.); CA047763 (to T.D.G.); and T32 HL007501 (L.H.)], the National Science Foundation [DGE-0947950 (L.H.)], and the Shakhmardan Yessenov Foundation, Kazakhstan (S.M.).