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The NR4A orphan nuclear receptors do not confer prednisolone resistance in pediatric acute lymphoblastic leukemia

Leukemia volume 28, pages 422–425 (2014)Cite this article

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Prednisolone is one of the principal chemotherapeutic drugs used to treat children with acute lymphoblastic leukemia (ALL). Resistance to prednisolone, both in vitro and in vivo, was shown to be of unfavorable prognostic value and has been used as a risk parameter in German COALL and BFM protocols as well as Dutch DCOG treatment protocols.1, 2, 3 In addition, ALL cells often acquire resistance to prednisolone at the time the leukemia relapses.4 Therapeutic intervention to overcome prednisolone resistance is therefore desirable.

Prednisolone serves as ligand for the cytosolic glucocorticoid receptor (GR or NR3C1). Binding of prednisolone conformationally changes the GR dispersing inactivating cochaperones, leading to homodimerization (Supplementary Figure 1). Hereafter, active GR orchestrates transcriptional regulation by binding to specific palindromic-negative or -positive glucocorticoid response elements (GRE) in the DNA, leading to gene repression or activation, respectively. Active GR can also sequester other transcription factors, such as AP-1 and nuclear factor (NF)-κB, thereby diminishing the transcriptional activation of AP-1 and NF-κB responsive genes. Eventually, prednisolone activates and deactivates numerous genes, ultimately inducing apoptosis. This process is impaired in prednisolone-resistant leukemic cells. Up to now the precise molecular mechanisms that denote prednisolone resistance in leukemic cells are unclear.

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Figure 1
Figure 2

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Acknowledgements

This work was supported by the Dutch Cancer Society (MLDB, RP, EMCR 2005-3313 and AMC 2008-4265) and NIH grant (MLDB, RP 5R37CA036401). The funding source had no role in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. We acknowledge MWJ Luijendijk (Erasmus MC, Rotterdam, Netherlands) and EF Petricoin (George Mason University, Manassas, USA) for the reverse-phase protein array analysis and IS Jerchel (Erasmus MC, Rotterdam, Netherlands) for her contribution to the lentiviral shRNA knockdown experiments. Professor Dr C de Vries, AMC, The Netherlands, is acknowledged for supplying the Nor1 antibody.

Author contributions

IMA designed and performed research, analyzed and interpreted data, and wrote the paper; ESRVDD performed experiments; RP and MLDB designed, analyzed and interpreted data, and revised the paper.

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  1. Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands

    I M Ariës, E S R van den Dungen, R Pieters & M L den Boer

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  1. I M Ariës
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  2. E S R van den Dungen
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  3. R Pieters
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  4. M L den Boer
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Correspondence to M L den Boer.

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Ariës, I., van den Dungen, E., Pieters, R. et al. The NR4A orphan nuclear receptors do not confer prednisolone resistance in pediatric acute lymphoblastic leukemia. Leukemia 28, 422–425 (2014). https://doi.org/10.1038/leu.2013.275

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