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Lookup NU author(s): Professor Simon BaileyORCiD, Dr Andrew Hall, Professor Andrew Pearson, Dr Chris RedfernORCiD
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Glucocorticoids are used in the treatment of acute lymphoblastic leukaemia (ALL) and chronic lymphocytic leukaemia (CLL) but many patients develop glucocorticoid resistance on relapse. The ligand-activated glucocorticoid receptor inhibits activity of the AP-1 transcription factor and the purpose of this study was to test the hypothesis that up-regulation or overexpression of AP1-binding activity may be an important mechanism of glucocorticoid resistance in ALL and CLL, In vitro sensitivity of patient blasts to prednisolone was measured using the MTT assay. AP-1 levels were quantified by gel shift analysis and Fos and Jun levels were compared by Western blotting. To test for a relationship between glucocorticoid sensitivity and glucocorticoid-induced changes in AP-1 binding activity, leukaemic blasts were also treated with prednisolone before analysis. Sensitivity of patient blasts to prednisolone varied, with IC50 values varying over a concentration range from 10(11) to 10(-4) M. Fos and Jun protein were detectable in all patient samples over a 300-fold range in relative expression, but did not correlate with prednisolone sensitivity. Gel-shift analysis demonstrated the presence of specific AP-1 -response-element-binding activity in all patient samples, but this did not correlate with prednisolone sensitivity. Furthermore, there was no relationship between prednisolone-induced changes in AP-1 binding activity and in vitro glucocorticoid resistance. These data show that glucocorticoid resistance is not associated with increased AP-1 binding activity or changes in the level of the Fos and Jun components of AP-1.
Author(s): Bailey, S., Hall, A. G., Pearson, A. D. J., Redfern, C. P. F.
Publication type: Article
Publication status: Published
Journal: Leukemia
Year: 2001
Volume: 15
Issue: 3
Pages: 391-397
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
URL: http://dx.doi.org/10.1038/sj.leu.2402039
DOI: 10.1038/sj.leu.2402039
PubMed id: 11237062
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