Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia

Abstract

Alternative splicing of the primary glucocorticoid receptor (GR) transcript, resulting in glucocorticoid receptor alpha GRa, glucocorticoid receptor beta GRb and glucocorticoid receptor gamma GRc, may influence glucocorticoid (GC) resistance in childhood leukemia. To test this hypothesis, we determined GRa/b protein and GRa/b/c mRNA expression levels in 43 initial acute lymphoblastic leukemia (iALL), 10 initial myeloid leukemia (iAML), 11 relapsed ALL (rALL) samples and one rAML sample. The results were correlated with in vitro GC resistance. GRa mRNA correlated with protein expression (q ¼ 0.39-0.56, Po0.05), but the protein to mRNA ratio was median 2.2-fold lower in rALL than in iALL (Po0.05). GRb mRNA was median 137-fold lower than GRa mRNA and correlated with GRa mRNA expression (q ¼ 0.71, Po0.0001). GRb could not be detected at the protein level. GRc accounted for a median of 2.8% (range 0.95-7.4%) of all GR transcripts. GRa (protein and mRNA) and GRb (mRNA) expressions or GRa/GRb ratios did not correlate with in vitro GC resistance in iALL, but GRc (mRNA) did (q ¼ 0.52, P ¼ 0.007). These results suggest that GRb is not involved in GC resistance in childhood leukemia. The association between GRc expression and in vitro GC resistance in iALL and the decreased protein/mRNA ratio in rALL, a subgroup resistant to GCs, warrants further exploration.

Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells

“…Furthermore, there is evidence of alterations in the expression levels of GR isoforms, which might contribute towards Gc resistance. GRb expression is increased in CEM cells and Gc-resistant CLL (Haarman et al 2004), although there was no correlation between Gc resistance and GRb expression in primary cells from patients with ALL (Haarman et al 2004) where there was a correlation with GRg expression. There is also increased GR-P expression in Gc-resistant tumour cells but not primary ALL cells (Tissing et al 2005).…”

Divergent Mechanisms of Glucocorticoid Resistance in Experimental Models of Pediatric Acute Lymphoblastic Leukemia

“…However, similar studies using primary patient samples have detected only isolated cases of somatic mutations in the GR, leading to poor glucocorticoid response (17,18). Although existing data are conflicting, the majority of studies have failed to associate glucocorticoid resistance in patient samples with either relative expression of the various isoforms of the receptor (19,20), polymorphisms within the coding region of the GR gene (18), or expression levels of cochaperone proteins associated with the GR (21).…”

Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance

“…99,100 However, there is little, if any, GRb expression in various hematopoietic tumors, which makes its role in resistance development questionable. 50,96,101 Indeed, Haarman et al 102 concluded that GRb is not involved in GC resistance in childhood leukemia, although a possible involvement of GRg in certain childhood leukemia subgroups could not be excluded. Whether GR-B affects sensitivity to GC-induced apoptosis in lymphoid malignancies is unknown.…”