Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia

Abstract

Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes.We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids. Methods: In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance. Results: No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research.

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

“…Mutations in the GC receptors (GRs) are commonly found in cell lines that have been selected for GC resistance by extended exposure to high drug concentrations, but are rarely found in primary ALL specimens and are not thought to contribute significantly to GC resistance in patients (Irving et al, 2005;Tissing et al, 2005). In lymphoid tumours, the ultimate effect of GC exposure is activation of apoptosis but it is important to remember that this differs from many other cell types where GCs in fact promote cell survival and proliferation (Zhang et al, 2007).…”

Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members

“…18,19 Their median age at diagnosis was 7 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) years. The diagnosis was established according to the World Health Organization classification.…”

“…4 A diminshed expression of glucocorticoid receptor (GR) mRNA levels has been found to be associated with some degree of in vitro resistance to prednisolone. 5 However, other studies have failed to show an association between the levels of GR protein expression and in vivo GC resistance, indicating that the overall levels of GR expression may be of minor importance for in vivo GC resistance in childhood ALL. 6 Two major apoptotic pathways, the mitochondrial and the death receptor-mediated pathways, have been described.…”

Pharmacogenomics of Open-Angle Glaucoma

“…Glucocorticoid receptors are present on the surface of trabecular meshwork cells, providing a possible mechanism for corticosteroid action on IOP (Weinreb et al, 1981). There are 6 well-known polymorphisms in the human glucocorticoid receptor gene (Tissing et al, 2005) at codon 766 (Koper et al, 1997); 5. a G→C substitution within intron 3 (Koper et al, 1997); 6. a G→T substitution within intron 4. (Koper et al, 1997).…”