Changes of glucocorticoid receptor isoforms expression in acute lymphoblastic leukemia correlate with glucocorticoid resistance

摘要

Alternative splicing of the glucocorticoid receptor (GR) gene results in several GR isoforms, we examined their expression (GR alpha, GR beta, GR gamma and GR-P) by real-time RT-PCR in glucocorticoid (GC) sensitive (CEM-C7), GC resistant (CEM-C1) cells and adult acute lymphoblastic leukemia (ALL) patients, to determine the association of OR isoform expression profiles and GC resistance in adult ALL patients. With GC treatment, OR levels in Cl cells showed no obvious changes. In C7 cells, the mRNA levels of GR alpha, GR beta and GR gamma first increased and then decreased, whereas OR-P mRNA had a continued rising trend. C7 cells had a higher GR alpha/GR gamma, lower GR alpha/GR-P and GR gamma/GR-P ratios than C1 cells (P<0.01). In adult ALL patients, GR gamma mRNA varied in different ALL stages (complete remission CR 15.82 vs. relapsed 8.21 vs. initial 1.93 P<0.05). It also did in the ratios between GR isoforms that GR alpha/GR gamma and GR alpha/GR-P in initial patients were higher than relapsed and CR (P<0.05), while GR gamma/GR-P in CR was higher than initial and relapsed patients (P<0.05). GR-P mRNA in T-ALL patients was much higher than that in B-ALL patients (P<0.05). Peripheral blood hemoglobin (HB) was positively correlated with GR alpha mRNA and OR-P mRNA (P<0.05), while white blood cells (WBC) negatively correlated with GR gamma mRNA (P<0.05). The present study demonstrates that OR autoinduction is more important to GC sensitivity than its basal level expression. GC sensitivity is also significantly correlated with GR alpha mRNA and mildly associated with GR beta mRNA expression. Both GR gamma mRNA and the ratios between GR isoforms (GR alpha/GR gamma, GR alpha/GR-P and GR gamma/GR-P) are correlated with ALL stages. The changes of mRNA expression levels of GR alpha, OR-P and GR gamma may provide valuable information for GC resistance. Peripheral blood HB and WBC affect OR isoform expression.