Glucocorticoids (GCs) are global regulators of gene transcription that act by binding to the glucocorticoid receptor, a ligand-activated transcription factor belonging to the nuclear receptor family. As synthetic GCs such as prednisolone or dexamethasone specifically induce cell cycle arrest and apoptosis in lymphoid cells, these drugs are widely used in the treatment of (childhood) acute lymphoblastic leukemia (ALL). GC resistance is a strong independent predictor of poor prognosis in the treatment of childhood ALL, but the underlying mechanisms remain poorly understood. In a previous study (Kuiper et al. Leukemia 2007) we determined by array-based SNP analysis that microdeletions affecting the anti-proliferative gene B-cell translocation gene 1 (BTG1) occurred in 4 out of 33 pre-B ALL cases. In our current study we show that prednisolone causes a 3-fold induction of BTG1 mRNA expression both in pre-B ALL cell lines and primary ALL, implicating BTG1 in cellular responses to GCs. Moreover, RNA-interference-mediated knockdown of BTG1 renders RS4;11 pre-B leukemia cells refractory to prednisolone-induced apoptosis. We show by genome-wide mRNA profiling that loss of BTG1 completely abrogates prednisolone-induced gene expression by downregulation of the glucocorticoid receptor NR3C1. Moreover, we present evidence showing that BTG1 is part of a nuclear receptor complex that regulates expression of NR3C1 and consequently GC responsiveness in ALL. In conclusion, we have identified BTG1 as an important determinant of GC sensitivity in ALL.

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