title: Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.
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.
authors.affiliation: Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Göllner
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.affiliation: Institute of Cancer Research (ICR), Molecular Pathology, London, UK.
authors.forename: Tino
authors.initials: T
authors.lastname: Schenk
authors.affiliation: Institute of Medical Informatics, University Hospital of Münster, Münster, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.affiliation: Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rohde
authors.affiliation: Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pabst
authors.affiliation: Department of Medicine A, Hematology and Oncology, University Hospital of Münster, Münster, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sauer
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Lerdrup
authors.affiliation: Goldyne Savad Institute of Gene Therapy, Jerusalem, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Tavor
authors.affiliation: Department of Medicine, Molecular Hematology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Stölzel
authors.affiliation: Department of Medicine, Molecular Hematology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Medicine, Molecular Hematology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Gerhard Domagk Institute of Pathology, University of Münster, Münster, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Plank Institute for Biophysical Chemistry, Goettingen, Germany.
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Pan
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Plank Institute for Biophysical Chemistry, Goettingen, Germany.|Bioanalytics, Institute for Clinical Chemistry, University Medical Center Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Institute of Medical Informatics, University Hospital of Münster, Münster, Germany.
authors.forename: Martin
authors.identifier: 0000-0001-9740-0788
authors.initials: M
authors.lastname: Dugas
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medicine III, University Hospital of Munich, Munich, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Research Unit Gene Vectors, Helmholtz Center Munich, Munich, Germany.
authors.forename: Binje
authors.initials: B
authors.lastname: Vick
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Research Unit Gene Vectors, Helmholtz Center Munich, Munich, Germany.
authors.forename: Irmela
authors.identifier: 0000-0003-1773-7677
authors.initials: I
authors.lastname: Jeremias
authors.affiliation: Department of Medicine A, Hematology and Oncology, University Hospital of Münster, Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Sylvester Comprehensive Cancer Center (UMHC), University of Miami Hospital and Clinics, Miami, Florida, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.affiliation: Department of Pathology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.affiliation: Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Müller
authors.affiliation: Department of Medicine, Molecular Hematology, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.affiliation: Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), Halle (Saale), Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D000069286:Bortezomib / Q000494:pharmacology; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D011728:Pyridones / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C577920:GSK-2816126; C490538:HOXB7 protein, human; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D018398:Homeodomain Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C097899:homeobox protein HOXA9; D003561:Cytarabine; D000069286:Bortezomib; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D046988:Proteasome Endopeptidase Complex