B cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic Ezh2 gain-of-function mutation (EZH2Y646F in human; Ezh2Y641F in mouse) is conditionally expressed. Expression of Ezh2Y641F in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Overexpression of the anti-apoptotic protein Bcl2, but not the oncoprotein Myc, or loss of the tumor suppressor protein p53 (encoded by Trp53 in mice) further accelerated lymphoma progression. Expression of the mutant Braf but not the mutant Nras oncoprotein further accelerated melanoma progression. Although expression of Ezh2Y641F globally increased the abundance of trimethylated Lys27 of histone H3 (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 that was associated with increased transcription at many loci. These results suggest that Ezh2Y641F induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.
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We thank the UNC Lineberger Animal Histopathology Core, Flow Cytometry Core, Animal Models Core and Microscopy Services Laboratory for technical assistance, and the Mouse Phase 1 Unit (D. Darr and J. Roques) for providing animals and expertise. This work was supported by the US National Cancer Institute grants R01-CA163896 (N.E.S.), CA185353 (N.E.S.) and T32-CA009156 (G.P.S.), the US National Institute of Aging grant R01-AG024379 (N.E.S.) and the US National Heart, Lung and Blood Institute grant F32-HL117581 (G.P.S.).
J.Q. and J.E.B. are inventors on a filed patent titled ‘Ezh2 inhibitors and uses thereof’. J.E.B. is now an employee, shareholder and executive at Novartis Pharmaceuticals.
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Souroullas, G., Jeck, W., Parker, J. et al. An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med 22, 632–640 (2016) doi:10.1038/nm.4092
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