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Göllner, S.* ; Oellerich, T.* ; Agrawal-Singh, S.* ; Schenk, T.* ; Klein, H.* ; Rohde, C.* ; Pabst, C.* ; Sauer, T.* ; Lerdrup, M.* ; Tavor, S.* ; Stoelzel, F.* ; Herold, S.* ; Ehninger, G.* ; Koehler, G.* ; Pan, K.* ; Urlaub, H.* ; Serve, H.* ; Dugas, M.* ; Spiekermann, K.* ; Vick, B. ; Jeremias, I. ; Berdel, W.E.* ; Hansen, K.* ; Zelent, A.* ; Wickenhauser, C.* ; Mueller, L.P.* ; Thiede, C.* ; Mueller-Tidow, C.*

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

Nat. Med. 23, 69-78 (2017)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 (HSP9O) and followed by proteasomal degradation of EZH2 in drug-resistant cells. Accordingly, inhibitors of HSP9O, 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Somatic Mutations; Gene Ezh2; Cells; Cancer; Transformation; Expression; Inhibitor; Therapy; Phosphorylation; Differentiation
Language
Publication Year 2017
Prepublished in Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 1078-8956
e-ISSN 1546-170X
Journal Nature medicine
Quellenangaben Volume: 23, Issue: 1, Pages: 69-78 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Research Unit Gene Vector (AGV)
POF-Topic(s) 30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Stem Cell and Neuroscience
Immune Response and Infection
PSP Element(s) G-506600-001
G-501590-001
DOI 10.1038/nm.4247
WOS ID WOS:000391646800015
PubMed ID 27941792
Erfassungsdatum 2016-12-31
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