Prednisolone exerts late mitogenic and biphasic effects on resistant acute lymphoblastic leukemia cells: Relation to early gene expression

Received 23 January 2009; received in revised form 13 March 2009; accepted 11 April 2009.

Abstract

Resistance or sensitivity to glucocorticoids is considered to be of crucial importance for disease prognosis in childhood acute lymphoblastic leukemia. Prednisolone exerted a delayed biphasic effect on the resistant CCRF-CEM leukemic cell line, necrotic at low doses and apoptotic at higher doses. At low doses, prednisolone exerted a pre-dominant mitogenic effect despite its induction on total cell death, while at higher doses, prednisolone's mitogenic and cell death effects were counterbalanced. Early gene microarray analysis revealed notable differences in 40 genes. The mitogenic/biphasic effects of prednisolone are of clinical importance in the case of resistant leukemic cells. This approach might lead to the identification of gene candidates for future molecular drug targets in combination therapy with glucocorticoids, along with early markers for glucocorticoid resistance.

Abbreviations: ALL, acute lymphoblastic leukemia, GR, glucocorticoid receptor, NF-κB, nuclear factor of kappa in B-cells, GC, glucocorticoid, MR, mineralocorticoid receptor, GRE, glucocorticoid response element, SNR, signal-to-noise ratio, TELiS database, transcription element listening system database, TFBMs, transcription factor binding motifs, FDR, false discovery rate, HCL, hierarchical clustering, SOM, self-organizing maps, Nt, counted number of cells at time tn, Nt−1, counted number of cells at time tn−1, PI, propidium iodide, SDS, sodium dodecyl sulfate, SSC, saline sodium citrate buffer, YY1, Yin and Yiang, SP1, stimulating protein 1, cap, cap signal for transcription initiation, MZF1, myeloid zinc finger protein 1, CP2, transcription factor CP2, CREB, cAMP-responsive element binding protein, CRE-BP1, CRE-binding protein 1, ZID, zinc finger with interaction domain, RREB1, Ras-responsive element binding protein 1, GM, geometric mean, qRT-PCR, real-time reverse transcription PCR, EGF, epidermal growth factor, EGFR, epidermal growth factor receptor, NK, natural killer cells

Keywords: Prednisolone, Biphasic, CCRF-CEM, Mitogenic, Differential gene expression

a Hematology/Oncology Unit, First Department of Pediatrics, University of Athens Medical School, “Aghia Sophia” Children's Hospital, Thivon & Levadias, 11527, Goudi, Athens, Greece

b University Research Institute for the Study and Treatment of Childhood Genetic and Malignant Diseases, Greece

c Choremeio Research Laboratory, First Department of Pediatrics, University of Athens Medical School, “Aghia Sophia” Children's Hospital, Athens, Greece

Corresponding author. Tel.: +30 210 746 7481; fax: +30 210 779 5538.

PII: S0145-2126(09)00188-X

doi:10.1016/j.leukres.2009.04.018

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