Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL.

Glucocorticoid (GC) resistance is an adverse prognostic factor in childhood acute lymphoblastic leukemia (ALL), but little is known about causes of GC resistance. Up-regulation of the glucocorticoid receptor (GR) has been suggested as an essential step to the induction of apoptosis in leukemic cells. In this study we investigated whether baseline mRNA expression levels of the 5 different GR promoter transcripts (1A1, 1A2, 1A3, 1B, and 1C) or differences in the degree of regulation of the GR or GR promoter transcripts upon GC exposure are related to GC resistance. Therefore, mRNA levels of the 5 GR promoter transcripts and of the GR were measured by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR; Taqman) technology in primary ALL cells prior to and after 3, 8, and 24 hours of prednisolone exposure. GR expression is induced upon GC exposure in primary ALL patient samples, which is opposite to what is found in tissues in which GCs do not induce apoptosis. GC resistance in childhood ALL cannot be attributed to an inability of resistant cells to up-regulate the expression of the GR upon GC exposure, nor to differences in GR promoter usage (at baseline and upon GC exposure).

[1]  D. Godfrey,et al.  Expression of the Glucocorticoid Receptor from the 1A Promoter Correlates with T Lymphocyte Sensitivity to Glucocorticoid-Induced Cell Death1 , 2004, The Journal of Immunology.

[2]  R. Kofler,et al.  Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance , 2004, Cell Death and Differentiation.

[3]  W. Vedeckis,et al.  Steroid-responsive sequences in the human glucocorticoid receptor gene 1A promoter. , 2004, Molecular endocrinology.

[4]  R. Kofler,et al.  Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells , 2004, Cell Death and Differentiation.

[5]  R. Pieters,et al.  Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia , 2004, Leukemia.

[6]  W. Vedeckis,et al.  Quantification and glucocorticoid regulation of glucocorticoid receptor transcripts in two human leukemic cell lines. , 2003, Biochemistry.

[7]  M. D. Boer,et al.  Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  S. Armstrong,et al.  Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. , 2003, Blood.

[9]  W. Vedeckis,et al.  Characterization of promoter 1B in the human glucocorticoid receptor gene , 2002, Molecular and Cellular Endocrinology.

[10]  M. Breslin,et al.  Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids. , 2001, Molecular endocrinology.

[11]  U. Certa,et al.  Expression profiling of glucocorticoid-treated T-ALL cell lines: rapid repression of multiple genes involved in RNA-, protein- and nucleotide synthesis , 2001, Oncogene.

[12]  M. Schrappe,et al.  Clinical Outcome of Patients with Childhood Acute Lymphoblastic Leukaemia and an Initial Leukaemic Blood Blast Count of Less than 1000 per Microliter , 2001, Klinische Padiatrie.

[13]  P. Sonneveld,et al.  Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells. , 2001, Cancer research.

[14]  J. Raemaekers,et al.  A novel method to compensate for different amplification efficiencies between patient DNA samples in quantitative real-time PCR. , 2001, The Journal of molecular diagnostics : JMD.

[15]  D. Bernhard,et al.  Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid‐induced apoptosis , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  G. Chrousos,et al.  Glucocorticoid Receptor β: View I , 1999, Trends in Endocrinology & Metabolism.

[17]  W. Liu,et al.  Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. , 1999, Cancer research.

[18]  R. Pieters,et al.  Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro-vivo correlations and cross-resistance to other drugs. , 1998, Blood.

[19]  T. Hongo,et al.  In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. , 1997, Blood.

[20]  J. Cidlowski,et al.  Downregulation of the Glucocorticoid Receptor. A Mechanism for Physiological Adaptation to Hormones a , 1994, Annals of the New York Academy of Sciences.

[21]  J. Cidlowski,et al.  Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid , 1994, Steroids.

[22]  J. Harmon,et al.  Differential autoregulation of glucocorticoid receptor expression in human T- and B-cell lines. , 1993, Endocrinology.

[23]  R. Pieters,et al.  Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia , 1991, The Lancet.

[24]  J. Harmon,et al.  Positive regulation of the glucocorticoid receptor in human T-cells sensitive to the cytolytic effects of glucocorticoids. , 1988, The Journal of biological chemistry.

[25]  W. Tissing,et al.  Expression of the glucocorticoid receptor and its isoforms in relation to glucocorticoid resistance in childhood acute lymphocytic leukemia. , 2005, Haematologica.

[26]  W. Tissing,et al.  Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia , 2003, Leukemia.

[27]  U. Wahn,et al.  Effect of Glucocorticoid Therapy on Glucocorticoid Receptors in Children with Autoimmune Diseases , 2001, Pediatric Research.

[28]  Chrousos,et al.  Glucocorticoid Receptor beta: View I. , 1999, Trends in endocrinology and metabolism: TEM.

[29]  Schmidt Tj,et al.  Autoregulation of corticosteroid receptors. How, when, where, and why? , 1994 .

[30]  T. Schmidt,et al.  Autoregulation of corticosteroid receptors. How, when, where, and why? , 1994, Receptor.

[31]  R. Pieters,et al.  In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions. , 1990, Blood.