In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types1,2,3,4,5. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma6,7,8,9,10. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes9,11,12,13. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.

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Gene Expression Omnibus

Data deposits

The gene expression data are accessible on GEO through accession number GSE40972 and the ChIP-seq data through accession number GSE40970.


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We acknowledge members of GlaxoSmithKline’s Platform Technology and Sciences group for reagent generation and sequencing, Ocimum Biosolutions for bioinformatic support, A. Anderson for statistical analysis, P. Hoffman for assistance with the manuscript, and all members of the Cancer Epigenetics Discovery Performance Unit for their guidance and support.

Author information


  1. Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA

    • Michael T. McCabe
    • , Heidi M. Ott
    • , Gopinath Ganji
    • , Susan Korenchuk
    • , Christine Thompson
    • , Glenn S. Van Aller
    • , Yan Liu
    • , Anthony Della Pietra III
    • , Louis V. LaFrance
    • , Mark Mellinger
    • , Celine Duquenne
    • , Xinrong Tian
    • , Ryan G. Kruger
    • , Charles F. McHugh
    • , William H. Miller
    • , Dashyant Dhanak
    • , Sharad K. Verma
    • , Peter J. Tummino
    •  & Caretha L. Creasy
  2. Platform Technology and Sciences, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA

    • Alan P. Graves
    • , Elsie Diaz
    •  & Martin Brandt


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M.T.M., G.G., R.G.K., C.F.M., M.B., S.K.V. and C.L.C. designed studies; M.T.M., H.M.O., S.K., C.T., G.S.V.A., E.D., Y.L., A.P.G., A.D.P., L.V.L., M.M., C.D., X.T. and C.F.M. performed research; M.T.M., G.G., R.G.K., A.P.G., C.F.M., S.K.V., W.H.M., D.D., P.J.T. and C.L.C. analysed data and M.T.M., G.G., R.G.K., A.P.G. and C.L.C. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Caretha L. Creasy.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Figures 1-18, Supplementary Methods, Supplementary Tables 1-5 and 8-9 – see separate files for Supplementary Tables 6 and 7.

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    Supplementary Table 6

    This file contains lists of significantly differentially exposed probe sets.

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    Supplementary Table 7

    This file contains H3K27me3 Chip-seq enriched regions.

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