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Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders

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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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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The authors declare no competing financial interests.

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Supplementary Tables 1–5 and Supplementary Figures 1–10 (PDF 1238 kb)

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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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