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Nat Med. 2017 Jan;23(1):69-78. doi: 10.1038/nm.4247. Epub 2016 Dec 12.

Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.

Author information

1
Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
2
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.
3
German Cancer Consortium (DKTK), Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
5
Institute of Cancer Research (ICR), Molecular Pathology, London, UK.
6
Institute of Medical Informatics, University Hospital of Münster, Münster, Germany.
7
Department of Medicine A, Hematology and Oncology, University Hospital of Münster, Münster, Germany.
8
Goldyne Savad Institute of Gene Therapy, Jerusalem, Israel.
9
Department of Medicine, Molecular Hematology, University Hospital Carl Gustav Carus, Dresden, Germany.
10
Gerhard Domagk Institute of Pathology, University of Münster, Münster, Germany.
11
Bioanalytical Mass Spectrometry Group, Max Plank Institute for Biophysical Chemistry, Goettingen, Germany.
12
Bioanalytics, Institute for Clinical Chemistry, University Medical Center Göttingen, Germany.
13
Department of Medicine III, University Hospital of Munich, Munich, Germany.
14
Research Unit Gene Vectors, Helmholtz Center Munich, Munich, Germany.
15
Sylvester Comprehensive Cancer Center (UMHC), University of Miami Hospital and Clinics, Miami, Florida, USA.
16
Department of Pathology, University Hospital of Halle (Saale), Halle (Saale), Germany.

Abstract

In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. Low EZH2 levels resulted in derepression of HOX genes, and knockdown of HOXB7 and HOXA9 in the resistant cells was sufficient to improve sensitivity to TKIs and cytotoxic drugs. The endogenous loss of EZH2 expression in resistant cells and primary blasts from a subset of relapsed AML patients resulted from enhanced CDK1-dependent phosphorylation of EZH2 at Thr487. This interaction was stabilized by heat shock protein 90 (HSP90) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP90, CDK1 and the proteasome prevented EZH2 degradation, decreased HOX gene expression and restored drug sensitivity. Finally, patients with reduced EZH2 levels at progression to standard therapy responded to the combination of bortezomib and cytarabine, concomitant with the re-establishment of EZH2 expression and blast clearance. These data suggest restoration of EZH2 protein as a viable approach to overcome treatment resistance in this AML patient population.

PMID:
27941792
DOI:
10.1038/nm.4247
[Indexed for MEDLINE]

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