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EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations


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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Figure 1: Biochemical and cellular mechanistic activity of GSK126.
Figure 2: GSK126 inhibits the proliferation of several EZH2 mutant lymphoma cell lines.
Figure 3: GSK126 induces transcriptional activation in sensitive cell lines.
Figure 4: In vivo inhibition of H3K27me3 and tumour growth response with GSK126.

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Primary accessions

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.


  1. Varambally, S. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695–1699 (2008)

    Article  CAS  ADS  Google Scholar 

  2. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002)

    Article  CAS  ADS  Google Scholar 

  3. Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003)

    Article  CAS  ADS  Google Scholar 

  4. Wagener, N. et al. Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer 10, 524 (2010)

    Article  Google Scholar 

  5. Takawa, M. et al. Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Sci. 102, 1298–1305 (2011)

    Article  CAS  Google Scholar 

  6. Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011)

    Article  CAS  ADS  Google Scholar 

  7. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet. 42, 181–185 (2010)

    Article  CAS  Google Scholar 

  8. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nature Genet. 43, 830–837 (2011)

    Article  CAS  Google Scholar 

  9. McCabe, M. T. et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc. Natl Acad. Sci. USA 109, 2989–2994 (2012)

    Article  CAS  ADS  Google Scholar 

  10. Ryan, R. J. et al. EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas. PLoS ONE 6, e28585 (2011)

    Article  CAS  ADS  Google Scholar 

  11. Sneeringer, C. J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107, 20980–20985 (2010)

    Article  CAS  ADS  Google Scholar 

  12. Wigle, T. J. et al. The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 585, 3011–3014 (2011)

    Article  CAS  Google Scholar 

  13. Yap, D. B. et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 117, 2451–2459 (2011)

    Article  CAS  Google Scholar 

  14. Diaz, E. et al. Development and validation of reagents and assays for EZH2 peptide and nucleosome high-throughput screens. J. Biomol. Screen. (2012)

  15. Schubert, H. L., Blumenthal, R. M. & Cheng, X. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem. Sci. 28, 329–335 (2003)

    Article  CAS  Google Scholar 

  16. Miranda, T. B. et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol. Cancer Ther. 8, 1579–1588 (2009)

    Article  CAS  Google Scholar 

  17. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009)

    Article  CAS  Google Scholar 

  18. Dyer, M. J., Fischer, P., Nacheva, E., Labastide, W. & Karpas, A. A new human B-cell non-Hodgkin’s lymphoma cell line (Karpas 422) exhibiting both t(14;18) and t(4;11) chromosomal translocations. Blood 75, 709–714 (1990)

    CAS  PubMed  Google Scholar 

  19. Al-Katib, A. M. et al. Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin. Cancer Res. 4, 1305–1314 (1998)

    CAS  PubMed  Google Scholar 

  20. Chou, R. H., Yu, Y. L. & Hung, M. C. The roles of EZH2 in cell lineage commitment. Am. J. Transl. Res. 3, 243–250 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Jankowska, A. M. et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118, 3932–3941 (2011)

    Article  CAS  Google Scholar 

  22. Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genet. 42, 722–726 (2010)

    Article  CAS  Google Scholar 

  23. Makishima, H. et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia 24, 1799–1804 (2010)

    Article  CAS  Google Scholar 

  24. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011)

    Article  CAS  Google Scholar 

  25. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010)

    Article  CAS  Google Scholar 

  26. Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nature Genet. 43, 875–878 (2011)

    Article  CAS  Google Scholar 

  27. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  28. Zang, C. et al. A clustering approach for identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 25, 1952–1958 (2009)

    Article  CAS  Google Scholar 

  29. Tornheim, K. Kinetic applications using high substrate and competitive inhibitor concentrations to determine K i or K m . Anal. Biochem. 221, 53–56 (1994)

    Article  CAS  Google Scholar 

  30. Yung-Chi, C. & Prusoff, W. H. Relationship between the inhibition constant (K 1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099–3108 (1973)

    Article  Google Scholar 

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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.

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Authors and Affiliations



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.

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Correspondence to Caretha L. Creasy.

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The authors declare no competing financial interests.

Supplementary information

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. (PDF 1990 kb)

Supplementary Table 6

This file contains lists of significantly differentially exposed probe sets. (XLSX 436 kb)

Supplementary Table 7

This file contains H3K27me3 Chip-seq enriched regions. (XLSX 15514 kb)

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McCabe, M., Ott, H., Ganji, G. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112 (2012).

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