Haarman E G, Kaspers G J L, Pieters R, Rottier M M A, Veerman A J P
Department of Pediatric Hematology/Oncology, VU University Medical Center, De Boelelaan, Amsterdam, The Netherlands.
Leukemia. 2004 Mar;18(3):530-7. doi: 10.1038/sj.leu.2403225.
Alternative splicing of the primary glucocorticoid receptor (GR) transcript, resulting in glucocorticoid receptor alpha GRalpha, glucocorticoid receptor beta GRbeta and glucocorticoid receptor gamma GRgamma, may influence glucocorticoid (GC) resistance in childhood leukemia. To test this hypothesis, we determined GRalpha/beta protein and GRalpha/beta/gamma 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. GRalpha mRNA correlated with protein expression (rho=0.39-0.56, P<0.05), but the protein to mRNA ratio was median 2.2-fold lower in rALL than in iALL (P<0.05). GRbeta mRNA was median 137-fold lower than GRalpha mRNA and correlated with GRalpha mRNA expression (rho=0.71, P<0.0001). GRbeta could not be detected at the protein level. GRgamma accounted for a median of 2.8% (range 0.95-7.4%) of all GR transcripts. GRalpha (protein and mRNA) and GRbeta (mRNA) expressions or GRalpha/GRbeta ratios did not correlate with in vitro GC resistance in iALL, but GRgamma (mRNA) did (rho=0.52, P=0.007). These results suggest that GRbeta is not involved in GC resistance in childhood leukemia. The association between GRgamma expression and in vitro GC resistance in iALL and the decreased protein/mRNA ratio in rALL, a subgroup resistant to GCs, warrants further exploration.
初级糖皮质激素受体（GR）转录本的可变剪接产生糖皮质激素受体α（GRα）、糖皮质激素受体β（GRβ）和糖皮质激素受体γ（GRγ），这可能会影响儿童白血病中的糖皮质激素（GC）抵抗。为了验证这一假设，我们测定了43例初发急性淋巴细胞白血病（iALL）、10例初发髓系白血病（iAML）、11例复发ALL（rALL）样本和1例rAML样本中的GRα/β蛋白及GRα/β/γ mRNA表达水平。结果与体外GC抵抗相关。GRα mRNA与蛋白表达相关（ρ=0.39 - 0.56，P<0.05），但rALL中蛋白与mRNA的比值中位数比iALL低2.2倍（P<0.05）。GRβ mRNA中位数比GRα mRNA低137倍，且与GRα mRNA表达相关（ρ=0.71，P<0.0001）。在蛋白水平未检测到GRβ。GRγ占所有GR转录本的中位数为2.8%（范围0.95 - 7.4%）。GRα（蛋白和mRNA）及GRβ（mRNA）表达或GRα/GRβ比值与iALL中的体外GC抵抗不相关，但GRγ（mRNA）相关（ρ=0.52，P=0.007）。这些结果表明GRβ不参与儿童白血病中的GC抵抗。iALL中GRγ表达与体外GC抵抗之间的关联以及rALL（对GC耐药的一个亚组）中蛋白/ mRNA比值的降低值得进一步探究。
