title: 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.
authors.affiliation: School of Medicine, University of Southampton, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Chase
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hidalgo-Curtis
authors.forename: Catherine
authors.initials: C
authors.lastname: Bryant
authors.forename: Amy V
authors.initials: AV
authors.lastname: Jones
authors.forename: Katherine
authors.initials: K
authors.lastname: Waghorn
authors.forename: Katerina
authors.initials: K
authors.lastname: Zoi
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.forename: Andrew
authors.initials: A
authors.lastname: Duncombe
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Francis H
authors.initials: FH
authors.lastname: Grand
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005809:Genes, Regulator; D016147:Genes, Tumor Suppressor; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D063151:Polycomb Repressive Complex 2; D011506:Proteins / Q000235:genetics; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D011506:Proteins; D014157:Transcription Factors; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine