The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia
Open accessAbstract
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.
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Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
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The polycomb group protein EZH2 is involved in progression of prostate cancer
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Genome-scale DNA methylation maps of pluripotent and differentiated cells
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Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
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Iwama, A. (2017) · Blood · doi:10.1182/blood-2017-02-739490 · Cited by 55
miR-451a abrogates treatment resistance in FLT3-ITD-positive acute myeloid leukemia.
Krakowsky, R. H. E., Wurm, A. A., Gerloff, D., Katzerke, C., Bräuer-Hartmann, D., Hartmann, J.-U., Wilke, F., Thiede, C., Müller-Tidow, C., Niederwieser, D., et al. (2018) · Blood Cancer Journal · doi:10.1038/s41408-018-0070-y · Cited by 18
Self-citationIntact-cell MALDI-ToF mass spectrometry for the authentication of drug-adapted cancer cell lines
Povey, J. F., Saintas, E., Aderemi, A. V., Rothweiler, F., Zehner, R., Dirks, W. G., Cinatl, J., Racher, A. J., Wass, M. N., Smales, C. M., et al. (2019) · Cells · doi:10.3390/cells8101194 · Cited by 5
Metadata
- Authors
- 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, W. E., Hansen, K., Zelent, A., Wickenhauser, C., Müller, L. P., Thiede, C., & Müller-Tidow, C.
- Venue
- Nature Medicine
- Published
- 2016-12-12
- Volume
- 23
- Issue
- 1
- Pages
- 69-78
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2567382369
- Cited by
- 257
- References
- 9
- FWCI
- 19.75
- Type
- journal article
- Language
- en
- Open access
- green
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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. https://doi.org/10.1038/nm.4247
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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