title: Elucidating the identity of resistance mechanisms to prednisolone exposure in acute lymphoblastic leukemia cells through transcriptomic analysis: A computational approach.
abstract: BACKGROUND
  It has been shown previously that glucocorticoids exert a dual mechanism of action, entailing cytotoxic, mitogenic as well as cell proliferative and anti-apoptotic responses, in a dose-dependent manner on CCRF-CEM cells at 72 h. Early gene expression response implies a dose-dependent dual mechanism of action of prednisolone too, something reflected on cell state upon 72 h of treatment.
  
  
  METHODS
  In this work, a generic, computational microarray data analysis framework is proposed, in order to examine the hypothesis, whether CCRF-CEM cells exhibit an intrinsic or acquired mechanism of resistance and investigate the molecular imprint of this, upon prednisolone treatment. The experimental design enables the examination of both the dose (0 nM, 10 nM, 22 uM, 700 uM) effect of glucocorticoid exposure and the dynamics (early and late, namely 4 h, 72 h) of the molecular response of the cells at the transcriptomic layer.
  
  
  RESULTS
  In this work, we demonstrated that CCRF-CEM cells may attain a mixed mechanism of response to glucocorticoids, however, with a clear preference towards an intrinsic mechanism of resistance. Specifically, at 4 h, prednisolone appeared to down-regulate apoptotic genes. Also, low and high prednisolone concentrations up-regulates genes related to metabolism and signal-transduction in both time points, thus favoring cell proliferative actions. In addition, regulation of NF-κB-related genes implies an inherent mechanism of resistance through the established link of NF-κB inflammatory role and GC-induced resistance. The analysis framework applied here highlights prednisolone-activated regulatory mechanisms through identification of early responding sets of genes. On the other hand, study of the prolonged exposure to glucocorticoids (72 h exposure) highlights the effect of homeostatic feedback mechanisms of the treated cells.
  
  
  CONCLUSIONS
  Overall, it appears that CCRF-CEM cells in this study exhibit a diversified, combined pattern of intrinsic and acquired resistance to prednisolone, with a tendency towards inherent resistant characteristics, through activation of different molecular courses of action.
authors.affiliation: School of Electrical and Computer Engineering, National Technical University of Athens, Athens, Greece.
authors.forename: Emmanouil G
authors.initials: EG
authors.lastname: Sifakis
authors.affiliation: First Department of Pediatrics, University of Athens, Choremeio Research Laboratory, Athens, Greece.
authors.forename: George I
authors.initials: GI
authors.lastname: Lambrou
authors.affiliation: Department of Digital Systems, University of Piraeus, Piraeus, Greece.
authors.forename: Andriana
authors.initials: A
authors.lastname: Prentza
authors.affiliation: First Department of Pediatrics, University of Athens, Choremeio Research Laboratory, Athens, Greece.
authors.forename: Spiros
authors.initials: S
authors.lastname: Vlahopoulos
authors.affiliation: School of Electrical and Computer Engineering, National Technical University of Athens, Athens, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Koutsouris
authors.affiliation: University Research Institute for Genetic and Malignant Diseases of Childhood, University of Athens, Athens, Greece.
authors.forename: Fotini
authors.initials: F
authors.lastname: Tzortzatou-Stathopoulou
authors.affiliation: Institute of Biological Research & Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Aristotelis A
authors.initials: AA
authors.lastname: Chatziioannou