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Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders

Nature Genetics volume 42, pages 722–726 (2010)Cite this article

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Abstract

Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

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Figure 1: Acquired EZH2 mutations associated with 7q aUPD.
Figure 2: Survival and expression analysis.
Figure 3: EZH2 mutations abrogate histone methyltransferase activity.

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Acknowledgements

This work was supported by a Leukemia Research specialist programme grant number 0282. T.E. was supported by the Dr. Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe e.V., Germany). A.H. was supported by the German José Carreras Foundation (H 03/01). We thank D. Reinberg and S. Orkin for providing reagents for the histone methyltransferase assays.

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Author notes

  1. Thomas Ernst and Andrew J Chase: These authors contributed equally to this work.

Authors and Affiliations

  1. Human Genetics Division, School of Medicine, University of Southampton, UK

    Thomas Ernst, Andrew J Chase, Joannah Score, Claire E Hidalgo-Curtis, Catherine Bryant, Amy V Jones, Katherine Waghorn, Fiona M Ross, Francis H Grand & Nicholas C P Cross

  2. Wessex Regional Genetics Laboratory, Salisbury, UK

    Thomas Ernst, Andrew J Chase, Joannah Score, Claire E Hidalgo-Curtis, Catherine Bryant, Amy V Jones, Katherine Waghorn, Fiona M Ross, Francis H Grand & Nicholas C P Cross

  3. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Thomas Ernst & Andreas Hochhaus

  4. Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece

    Katerina Zoi

  5. III. Medizinische Universitätsklinik, Medizinische Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany

    Andreas Reiter

  6. Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ)-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

    Hans G Drexler

  7. Department of Haematology, Southampton General Hospital, Southampton, UK

    Andrew Duncombe

  8. Hematology Department, Hospital Clínic, Insititut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

    Francisco Cervantes

  9. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    David Oscier

  10. Leukaemia and Lymphoma Research,

    Jacqueline Boultwood

  11. Molecular Haematology Unit, John Radcliffe Hospital, Oxford, UK

    Jacqueline Boultwood

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  1. Thomas Ernst
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Contributions

T.E., A.J.C., F.H.G. and N.C.P.C. designed the study. T.E., A.J.C., J.S., C.E.H.-C., C.B., A.V.J. and K.W. performed the laboratory analysis. K.Z., F.M.R., A.R., A.H., A.D., F.C., D.O. and J.B. provided clinical samples and data. H.G.D. provided the cell lines and cell line DNA. N.C.P.C. wrote the initial draft, and all authors contributed to the final version.

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Correspondence to Nicholas C P Cross.

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Ernst, T., Chase, A., Score, J. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 42, 722–726 (2010). https://doi.org/10.1038/ng.621

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