Souroullas, George P.Jeck, William R.Parker, Joel S.Simon, Jeremy M.Liu, Jie-YuPaulk, JoshiawaXiong, JessieClark, Kelly S.Fedoriw, YuriQi, JunBurd, Christin E.Bradner, James ESharpless, Norman E.2016-12-022016Souroullas, G. P., W. R. Jeck, J. S. Parker, J. M. Simon, J. Liu, J. Paulk, J. Xiong, et al. 2016. “An oncogenic Ezh2 mutation cooperates with particular genetic alterations to induce tumors in mice and redistributes H3K27 trimethylation throughout the genome.” Nature medicine 22 (6): 632-640. doi:10.1038/nm.4092. http://dx.doi.org/10.1038/nm.4092.1078-8956http://nrs.harvard.edu/urn-3:HUL.InstRepos:29626040B-cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase, 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 (Y646F in human, Y641F in the mouse) can be conditionally expressed. Expression of Ezh2Y641F in mouse B-cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively. Bcl2 overexpression or p53 loss, but not c-Myc overexpression, further accelerated lymphoma progression, and expression of mutant B-Raf but not mutant N-Ras further accelerated melanoma progression. Although expression of Ezh2Y641F increased abundance of global H3K27 trimethylation (H3K27me3), it also caused a widespread redistribution of this repressive mark, including a loss of H3K27me3 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.en-USJournal Article2016-12-0210.1038/nm.4092