Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children.
BACKGROUND
Sensitivity of leukemic blasts to glucocorticoid is one of the important prognostic factors for pediatric acute lymphoblastic leukemia (ALL). Alternative splicing of the glucocorticoid receptor (GR) gene results in several isoforms. We examined an association of the expression pattern of GR isoforms in leukemic blasts with their sensitivity to glucocorticoid in childhood ALL.


METHODS
The relative mRNA expression of GRalpha, GRbeta, GRgamma, and GR-P was determined in leukemic blasts of 23 childhood ALL at initial presentation and of 14 ALL cell lines by quantitative RT-PCR. Glucocorticoid-sensitivity of leukemic blasts was determined by counting apoptotic cells with flow cytometry after 6-hr incubation with prednisolone (PSL).


RESULTS
The relative expression of GRalpha mRNA was significantly higher in blasts of B-precursor ALL than those of others (13.6 vs. 2.24, P = 0.015), while those of GRalpha, GRbeta, and GRgamma showed no difference. GRbeta/GRalpha ratios were significantly lower in B-precursor ALL than others (0.80 vs. 4.64, P = 0.035). The proportions of apoptotic cells after PSL exposure were inversely correlated with the GRbeta/GRalpha ratios in ALL cell lines (r = -0.612, P = 0.020). PSL administration induced apoptosis efficiently in leukemic blasts with low GRbeta/GRalpha ratios compared with those of high ratios (cell lines: 4.93% vs. 1.90%, P = 0.013, primary leukemia: 11.7% vs. 3.6%, P = 0.037).


CONCLUSIONS
The amounts of GR isoform mRNA in leukemic blasts were closely correlated with sensitivity to glucocorticoid exposure. The mRNA expression pattern of GR isoforms at initial presentation may provide valuable information for prognosis in children with newly diagnosed ALL.
Koga
Yuhki
Y
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. yuuki-k@pediatr.med.kyushu-u.ac.jp
Matsuzaki
Akinobu
A
Suminoe
Aiko
A
Hattori
Hiroyoshi
H
Kanemitsu
Satomi
S
Hara
Toshiro
T
D000293:Adolescent; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics* / Q000276:immunology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007223:Infant; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D011379:Prognosis; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011965:Receptors, Glucocorticoid