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 Vick; Irmela Jeremias; Wolfgang E Berdel; Klaus Hansen; Arthur Zelent; Claudia Wickenhauser; Lutz P Müller; Christian Thiede; Carsten Müller-Tidow

doi:10.1038/nm.4247

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 Zelent, Claudia Wickenhauser, Lutz P Müller, Christian Thiede, Carsten Müller-Tidow

100 Citations (Scopus)

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 language	English
Journal	Nature Medicine
Volume	23
Issue number	1
Pages (from-to)	69-78
Number of pages	10
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.4247
Publication status	Published - 1 Jan 2017

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Göllner, S., Oellerich, T., Agrawal-Singh, S., Schenk, T., Klein, H.-U., Rohde, C., Pabst, C., Sauer, T., Lerdrup, M., Tavor, S., Stölzel, F., Herold, S., Ehninger, G., Köhler, G., Pan, K.-T., Urlaub, H., Serve, H., Dugas, M., Spiekermann, K., ... 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

Göllner, S, Oellerich, T, Agrawal-Singh, S, Schenk, T, Klein, H-U, Rohde, C, Pabst, C, Sauer, T, Lerdrup, M, Tavor, S, Stölzel, F, Herold, S, Ehninger, G, Köhler, G, Pan, K-T, Urlaub, H, Serve, H, Dugas, M, Spiekermann, K, Vick, B, Jeremias, I, Berdel, WE, Hansen, K, Zelent, A, 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

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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.",

author = "Stefanie G{\"o}llner and Thomas Oellerich and Shuchi Agrawal-Singh and Tino Schenk and Hans-Ulrich Klein and Christian Rohde and Caroline Pabst and Tim Sauer and Mads Lerdrup and Sigal Tavor and Friedrich St{\"o}lzel and Sylvia Herold and Gerhard Ehninger and Gabriele K{\"o}hler and Kuan-Ting Pan and Henning Urlaub and Hubert Serve and Martin Dugas and Karsten Spiekermann and Binje Vick and Irmela Jeremias and Berdel, {Wolfgang E} and Klaus Hansen and Arthur Zelent and Claudia Wickenhauser and M{\"u}ller, {Lutz P} and Christian Thiede and Carsten M{\"u}ller-Tidow",

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T1 - Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia

AU - Göllner, Stefanie

AU - Oellerich, Thomas

AU - Agrawal-Singh, Shuchi

AU - Schenk, Tino

AU - Klein, Hans-Ulrich

AU - Rohde, Christian

AU - Pabst, Caroline

AU - Sauer, Tim

AU - Lerdrup, Mads

AU - Tavor, Sigal

AU - Stölzel, Friedrich

AU - Herold, Sylvia

AU - Ehninger, Gerhard

AU - Köhler, Gabriele

AU - Pan, Kuan-Ting

AU - Urlaub, Henning

AU - Serve, Hubert

AU - Dugas, Martin

AU - Spiekermann, Karsten

AU - Vick, Binje

AU - Jeremias, Irmela

AU - Berdel, Wolfgang E

AU - Hansen, Klaus

AU - Zelent, Arthur

AU - Wickenhauser, Claudia

AU - Müller, Lutz P

AU - Thiede, Christian

AU - Müller-Tidow, Carsten

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

U2 - 10.1038/nm.4247

DO - 10.1038/nm.4247

M3 - Journal article

C2 - 27941792

SN - 1078-8956

VL - 23

SP - 69

EP - 78

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -

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

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