English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

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

Göllner, S., Oellerich, T., Agrawal-Singh, S., Schenk, T., Klein, H. U., Rohde, C., et al. (2017). Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nature Medicine, 23(1), 69-78.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-58AE-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-58B3-2
Genre: Journal Article

Files

show Files
hide Files
:
2389956.pdf (Publisher version), 3MB
 
File Permalink:
-
Name:
2389956.pdf
Description:
-
Visibility:
Restricted (Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute), Göttingen; )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
2389956_Suppl.pdf (Supplementary material), 19MB
Name:
2389956_Suppl.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show

Creators

show
hide
 Creators:
Göllner, S., Author
Oellerich, T., Author
Agrawal-Singh, S., Author
Schenk, T., Author
Klein, H. U., Author
Rohde, C., Author
Pabst, C., Author
Sauer, T., Author
Lerdrup, M., Author
Tavor, S., Author
Stölzel, F., Author
Herold, S., Author
Ehninger, G., Author
Köhler, G., Author
Pan, K. T.1, Author              
Urlaub, H.1, Author              
Serve, H., Author
Dugas, M., Author
Spiekermann, K., Author
Vick, B., Author
Jeremias, I., AuthorBerdel, W. E., AuthorHansen, K., AuthorZelent, A., AuthorWickenhauser, C., AuthorMüller, L. P., AuthorThiede, C., AuthorMüller-Tidow, C., Author more..
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              

Content

show
hide
Free keywords: -
 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 (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.

Details

show
hide
Language(s): eng - English
 Dates: 2016-12-122017-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: CoNE: 1038/nm.4247
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Nature Medicine
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 23 (1) Sequence Number: - Start / End Page: 69 - 78 Identifier: -