title: Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies.
abstract: Polycomb repressive complex 2 (PRC2) is involved in trimethylation of histone H3 lysine 27 (H3K27), chromatin condensation and transcriptional repression. The silencing function of PRC2 complex is mostly attributed to its intrinsic activity for methylating H3K27. Unlike in B-cell lymphomas, enhancer of zeste homolog 2 (EZH2) mutations in myeloid malignancies are inactivating/hypomorphic. When we assessed the mutational status in myeloid malignancies (N=469 cases examined), we found EZH2 and EED/SUZ12 mutations in 8% and 3.3% of cases, respectively. In addition to mutant cases, reduced EZH2 expression was also found in 78% cases with hemizygous deletion (-7/del7q cases involving EZH2 locus) and 41% of cases with diploid chromosome 7, most interestingly cases with spliceosomal mutations (U2AF1/SRSF2 mutations; 63% of cases). EZH2 mutations were characterized by decreased H3K27 trimethylation and increased chromatin relaxation at specific gene loci accompanied by higher transcriptional activity. One of the major downstream target is HOX gene family, involved in the regulation of stem cell self-renewal. HOXA9 was found to be overexpressed in cases with decreased EZH2 expression either by EZH2/spliceosomal mutations or because of -7/del7q. In summary, our results suggest that loss of gene repression through a variety of mutations resulting in reduced H3K27 trimethylation may contribute to leukemogenesis.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Khan
authors.forename: A M
authors.initials: AM
authors.lastname: Jankowska
authors.forename: R
authors.initials: R
authors.lastname: Mahfouz
authors.forename: A J
authors.initials: AJ
authors.lastname: Dunbar
authors.forename: Y
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: N
authors.initials: N
authors.lastname: Hosono
authors.forename: Z
authors.initials: Z
authors.lastname: Hu
authors.forename: V
authors.initials: V
authors.lastname: Cheriyath
authors.forename: S
authors.initials: S
authors.lastname: Vatolin
authors.forename: B
authors.initials: B
authors.lastname: Przychodzen
authors.forename: F J
authors.initials: FJ
authors.lastname: Reu
authors.forename: Y
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: C
authors.initials: C
authors.lastname: O'Keefe
authors.forename: M A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: A F
authors.initials: AF
authors.lastname: List
authors.forename: A R
authors.initials: AR
authors.lastname: Moliterno
authors.forename: M A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: H
authors.initials: H
authors.lastname: Makishima
mesh_terms: D015153:Blotting, Western; D002897:Chromosomes, Human, Pair 7; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D019337:Hematologic Neoplasms / Q000235:genetics*; D006657:Histones / Q000235:genetics*; D006801:Humans; D009154:Mutation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2