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Erg and AP-1 as determinants of glucocorticoid response in acute lymphoblastic leukemia

Oncogene volume 32, pages 3039–3048 (2013)Cite this article

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Abstract

Glucocorticoids (GCs) are among the most widely prescribed medications in clinical practice. The beneficial effects of GCs in acute lymphoblastic leukemia (ALL) are based on their ability to induce apoptosis, but the underlying transcriptional mechanisms remain poorly defined. Computational modeling has enormous potential in the understanding of biological processes such as apoptosis and the discovery of novel regulatory mechanisms. We here present an integrated analysis of gene expression kinetic profiles using microarrays from GC sensitive and resistant ALL cell lines and patients, including newly generated and previously published data sets available from the Gene Expression Omnibus. By applying time-series clustering analysis in the sensitive ALL CEM-C7–14 cells, we identified 358 differentially regulated genes that we classified into 15 kinetic profiles. We identified GC response element (GRE) sequences in 33 of the upregulated known or potential GC receptor (GR) targets. Comparative study of sensitive and resistant ALL showed distinct gene expression patterns and indicated unexpected similarities between sensitivity-restored and resistant ALL. We found that activator protein 1 (AP-1), Ets related gene (Erg) and GR pathways were differentially regulated in sensitive and resistant ALL. Erg protein levels were substantially higher in CEM-C1–15-resistant cells, c-Jun was significantly induced in sensitive cells, whereas c-Fos was expressed at low levels in both. c-Jun was recruited on the AP-1 site on the Bim promoter, whereas a transient Erg occupancy on the GR promoter was detected. Inhibition of Erg and activation of GR lead to increased apoptosis in both sensitive and resistant ALL. These novel findings significantly advance our understanding of GC sensitivity and can be used to improve therapy of leukemia.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

GC:

glucocorticoid

GR:

glucocorticoid receptor

GRE:

glucocorticoid response element

Bcl-2:

B-cell lymphoma 2

Dex:

dexamethasone

Erg:

Ets related gene

p-Jun:

phospho-c-Jun

AP-1:

activator protein 1.

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Acknowledgements

We thank Professor Sharrocks and Dr Demonacos for helpful comments and criticisms, Dr Tournier for reagents and the Faculty of Life Sciences Core Facility of the University of Manchester for help with microarray analysis.

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  1. J-M Schwartz and M Krstic-Demonacos: These authors contributed equally to this work.

Authors and Affiliations

  1. Faculty of Life Sciences, The University of Manchester, Manchester, UK

    D W-C Chen, J-M Schwartz & M Krstic-Demonacos

  2. School of Medicine, The University of Manchester, Manchester, UK

    V Saha & J-Z Liu

  3. Manchester Institute of Biotechnology, Faculty of Life Sciences, The University of Manchester, Manchester, UK

    D W-C Chen & J-M Schwartz

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  1. D W-C Chen
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  2. V Saha
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Correspondence to J-M Schwartz or M Krstic-Demonacos.

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Chen, DC., Saha, V., Liu, JZ. et al. Erg and AP-1 as determinants of glucocorticoid response in acute lymphoblastic leukemia. Oncogene 32, 3039–3048 (2013). https://doi.org/10.1038/onc.2012.321

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