Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor
Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor
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DOI：
10.1182/blood-2004-05-2023
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Lock, RB
中科院分区：
文献类型：
--
作者：
Bachmann, PS;Gorman, R;Lock, RB
糖皮质激素是治疗儿童急性淋巴细胞白血病（ALL）最有效的药物之一，患者对治疗的反应是长期预后的重要决定因素。尽管其临床意义，糖皮质激素抵抗的淋巴系统恶性肿瘤的分子基础仍然知之甚少。我们最近开发了一种高度临床相关的儿童ALL实验模型，其中在非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠中建立了原发性儿童ALL活检作为异种移植物。一组这些异种移植物对糖皮质激素地塞米松的体内和体外反应反映了它们来源的患者的结果。在这份报告中，我们表明，糖皮质激素抵抗的B细胞前体（BCP）ALL异种移植物是由于糖皮质激素受体（GR）的下调，也没有缺陷！此外，地塞米松诱导的GR从细胞质到细胞核的易位在所有异种移植物中是相当的。然而，当异种移植细胞暴露于地塞米松时，糖皮质激素抵抗与仅BH 3促凋亡蛋白Bim的深度衰减诱导相关。这些结果表明BCP ALL异种移植物中的地塞米松抗性发生在配体诱导的GR核转位的下游，但在Bim的上游。诱导(c)2005年美国血液学会
Glucocorticoids are among the most effective agents used in the treatment of childhood acute lymphoblastic leukemia (ALL), and patient response to treatment is an important determinant of long-term outcome. Despite its clinical significance, the molecular basis of glucocorticoid resistance in lymphoid malignancies is still poorly understood. We have recently developed a highly clinically relevant experimental model of childhood ALL, in which primary childhood ALL biopsies were established as xenografts in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The in vivo and in vitro responses of a panel of these xenografts to the glucocorticoid, dexamethasone, reflected the outcome of the patients from whom they were derived. In this report we show that glucocorticoid resistance in B-cell precursor (BCP) ALL xenografts was not due to down-regulation of the glucocorticoid receptor (GR) nor to defective! ligand binding of the GR. Moreover, dexamethasone-induced GR translocation from the cytoplasm to the nucleus was comparable in all xenografts. However, glucocorticoid resistance was associated with profoundly attenuated induction of the BH3-only proapoptotic protein, Bim, when xenograft cells were exposed to dexamethasone. These results show that dexamethasone resistance in BCP ALL xenografts occurs downstream of ligand-induced nuclear translocation of the GR, but upstream of Bim. induction. (c) 2005 by The American Society of Hematology