Oncotarget

Research Papers:

The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia

Nikos Papakonstantinou, Stavroula Ntoufa, Elisavet Chartomatsidou, Konstantia Kotta, Andreas Agathangelidis, Lefki Giassafaki, Tzeni Karamanli, Panagiota Bele, Theodoros Moysiadis, Panagiotis Baliakas, Lesley Ann Sutton, Niki Stavroyianni, Achilles Anagnostopoulos, Antonios M. Makris, Paolo Ghia, Richard Rosenquist and Kostas Stamatopoulos _

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Oncotarget. 2016; 7:35946-35959. https://doi.org/10.18632/oncotarget.9371

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Abstract

Nikos Papakonstantinou1,2,*, Stavroula Ntoufa1,2,*, Elisavet Chartomatsidou1, Konstantia Kotta1, Andreas Agathangelidis3, Lefki Giassafaki1, Tzeni Karamanli1, Panagiota Bele1, Theodoros Moysiadis1, Panagiotis Baliakas2, Lesley Ann Sutton2, Niki Stavroyianni4, Achilles Anagnostopoulos4, Antonios M. Makris1, Paolo Ghia3, Richard Rosenquist2 and Kostas Stamatopoulos1,2,4

1 Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece

2 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

3 Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy

4 Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

* These authors have contributed equally to this work

Correspondence to:

Kostas Stamatopoulos, email:

Keywords: CLL, EZH2, apoptosis, proliferation, inhibitors

Received: November 09, 2015 Accepted: April 24, 2016 Published: May 14, 2016

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.


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