title: The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia.
abstract: The histone methyltransferase EZH2 induces gene repression through trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 overexpression has been reported in many types of cancer and associated with poor prognosis. Here we investigated the expression and functionality of EZH2 in chronic lymphocytic leukemia (CLL). Aggressive cases with unmutated IGHV genes (U-CLL) displayed significantly higher EZH2 expression compared to indolent CLL cases with mutated IGHV genes (M-CLL); furthermore, in U-CLL EZH2 expression was upregulated with disease progression. Within U-CLL, EZH2high cases harbored significantly fewer (p = 0.033) TP53 gene abnormalities compared to EZH2low cases. EZH2high cases displayed high H3K27me3 levels and increased viability suggesting that EZH2 is functional and likely confers a survival advantage to CLL cells. This argument was further supported by siRNA-mediated downmodulation of EZH2 which resulted in increased apoptosis. Notably, at the intraclonal level, cell proliferation was significantly associated with EZH2 expression. Treatment of primary CLL cells with EZH2 inhibitors induced downregulation of H3K27me3 levels leading to increased cell apoptosis. In conclusion, EZH2 is overexpressed in adverse-prognosis CLL and associated with increased cell survival and proliferation. Pharmacologic inhibition of EZH2 catalytic activity promotes apoptosis, highlighting EZH2 as a novel potential therapeutic target for specific subgroups of patients with CLL.
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.|Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Nikos
authors.initials: N
authors.lastname: Papakonstantinou
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.|Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Ntoufa
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Chartomatsidou
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Konstantia
authors.initials: K
authors.lastname: Kotta
authors.affiliation: Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Andreas
authors.initials: A
authors.lastname: Agathangelidis
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Lefki
authors.initials: L
authors.lastname: Giassafaki
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Tzeni
authors.initials: T
authors.lastname: Karamanli
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Bele
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Moysiadis
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Baliakas
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lesley Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Stavroyianni
authors.affiliation: Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Achilles
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
authors.forename: Antonios M
authors.initials: AM
authors.lastname: Makris
authors.affiliation: Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.|Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
mesh_terms: D000368:Aged; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D006657:Histones; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D016159:Tumor Suppressor Protein p53; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: CLL; EZH2; apoptosis; inhibitors; proliferation