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Apoptosis

Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia

Leukemia volume 23, pages 746–752 (2009)Cite this article

Abstract

Glucocorticoids (GCs) induce apoptosis in lymphoid lineage cells and are therefore used in the therapy of acute lymphoblastic leukemia (ALL) and related malignancies. MicroRNAs (miRNAs) and the related mirtrons are ∼22 nucleotide RNAs derived from polymerase-II transcripts and implicated in the control of essential biological functions, including apoptosis. Whether GCs regulate miRNA-encoding transcription units is unknown. We investigated miRNA/mirtron expression and GC regulation in 8 leukemia/lymphoma in vitro models and 13 ALL children undergoing systemic GC monotherapy using a combination of expression profiling techniques, real time reverse transcription (RT)-PCR and northern blotting to detect mature miRNAs and/or their precursors. We found that mature miRNA regulations can be inferred from expression data of their host genes. Although a simple miRNA-initiated canonical pathway to GC-induced apoptosis or cell cycle arrest did not emerge, we identified several miRNAs/mirtrons that were regulated by GC in patients and cell lines, including the myeloid-specific miR-223 and the apoptosis and cell cycle arrest-inducing miR15∼16 clusters. In an in vitro model, overexpression of miR15b∼16 mimics increased and silencing by miR15b∼16 inhibitors decreased GC sensitivity. Thus, the observed complex changes in miRNA/mirtron expression during GC treatment might contribute to the anti-leukemic GC effects in a cell context-dependent manner.

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Acknowledgements

We thank Drs S Geley, A Hüttenhofer, B Meister and S Schmidt for stimulating discussions; M Brunner, A Kofler, S Lobenwein and C Mantinger for technical help; and MK Occhipinti-Bender for editing. This study was supported by grants from the Austrian Science Fund (SFB-F021, P18747, P18571) and the Austrian Ministry for Education, Science and Culture (GENAU-Ch.I.L.D.).

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Author notes

  1. J Rainer and C Ploner: These authors contributed equally to this work.

Authors and Affiliations

  1. Tyrolean Cancer Research Institute, Innsbruck, Austria

    J Rainer, S Jesacher, M Eduardoff, M Mansha, M Wasim, H Niederegger & R Kofler

  2. Division of Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

    C Ploner, M Mansha, M Wasim & R Kofler

  3. Division of Genomics and RNomics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

    A Ploner

  4. Children's Cancer Research Institute and St Anna Kinderspital, Vienna, Austria

    R Panzer-Grümayer

  5. Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria

    Z Trajanoski

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  1. J Rainer
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Correspondence to R Kofler.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Rainer, J., Ploner, C., Jesacher, S. et al. Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia. Leukemia 23, 746–752 (2009). https://doi.org/10.1038/leu.2008.370

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