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

Stefanie Göllner, Thomas Oellerich, Shuchi Agrawal-Singh, Tino Schenk, Hans Ulrich Klein, Christian Rohde, Caroline Pabst, Tim Sauer, Mads Lerdrup, Sigal Tavor, Friedrich Stölzel, Sylvia Herold, Gerhard Ehninger, Gabriele Köhler, Kuan Ting Pan, Henning Urlaub, Hubert Serve, Martin Dugas, Karsten Spiekermann, Binje VickIrmela Jeremias, Wolfgang E. Berdel, Klaus Hansen, Arthur Z Zelent, Claudia Wickenhauser, Lutz P. Müller, Christian Thiede, Carsten Müller-Tidow

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalNature Medicine
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2017

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Multiple Drug Resistance
Acute Myeloid Leukemia
HSP90 Heat-Shock Proteins
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Degradation
Phosphorylation
Proteins
Gene Knockdown Techniques
Cytarabine
Proteasome Endopeptidase Complex
Gene expression
Histones
Restoration
Myeloid Cells
Genes
Cells
histone methyltransferase
Therapeutics
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Göllner, S., Oellerich, T., Agrawal-Singh, S., Schenk, T., Klein, H. U., Rohde, C., ... Müller-Tidow, C. (2017). Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nature Medicine, 23(1), 69-78. https://doi.org/10.1038/nm.4247

Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. / Göllner, Stefanie; Oellerich, Thomas; Agrawal-Singh, Shuchi; Schenk, Tino; Klein, Hans Ulrich; Rohde, Christian; Pabst, Caroline; Sauer, Tim; Lerdrup, Mads; Tavor, Sigal; Stölzel, Friedrich; Herold, Sylvia; Ehninger, Gerhard; Köhler, Gabriele; Pan, Kuan Ting; Urlaub, Henning; Serve, Hubert; Dugas, Martin; Spiekermann, Karsten; Vick, Binje; Jeremias, Irmela; Berdel, Wolfgang E.; Hansen, Klaus; Zelent, Arthur Z; Wickenhauser, Claudia; Müller, Lutz P.; Thiede, Christian; Müller-Tidow, Carsten.

In: Nature Medicine, Vol. 23, No. 1, 01.01.2017, p. 69-78.

Research output: Contribution to journalArticle

Göllner, S, Oellerich, T, Agrawal-Singh, S, Schenk, T, Klein, HU, Rohde, C, Pabst, C, Sauer, T, Lerdrup, M, Tavor, S, Stölzel, F, Herold, S, Ehninger, G, Köhler, G, Pan, KT, Urlaub, H, Serve, H, Dugas, M, Spiekermann, K, Vick, B, Jeremias, I, Berdel, WE, Hansen, K, Zelent, AZ, Wickenhauser, C, Müller, LP, Thiede, C & Müller-Tidow, C 2017, 'Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia', Nature Medicine, vol. 23, no. 1, pp. 69-78. https://doi.org/10.1038/nm.4247
Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C et al. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nature Medicine. 2017 Jan 1;23(1):69-78. https://doi.org/10.1038/nm.4247
Göllner, Stefanie ; Oellerich, Thomas ; Agrawal-Singh, Shuchi ; Schenk, Tino ; Klein, Hans Ulrich ; Rohde, Christian ; Pabst, Caroline ; Sauer, Tim ; Lerdrup, Mads ; Tavor, Sigal ; Stölzel, Friedrich ; Herold, Sylvia ; Ehninger, Gerhard ; Köhler, Gabriele ; Pan, Kuan Ting ; Urlaub, Henning ; Serve, Hubert ; Dugas, Martin ; Spiekermann, Karsten ; Vick, Binje ; Jeremias, Irmela ; Berdel, Wolfgang E. ; Hansen, Klaus ; Zelent, Arthur Z ; Wickenhauser, Claudia ; Müller, Lutz P. ; Thiede, Christian ; Müller-Tidow, Carsten. / Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. In: Nature Medicine. 2017 ; Vol. 23, No. 1. pp. 69-78.
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