Bachmann Petra S, Gorman Rosemary, Papa Rachael A, Bardell Jane E, Ford Jette, Kees Ursula R, Marshall Glenn M, Lock Richard B
Children's Cancer Institute Australia for Medical Research, The University of New South Wales, Sydney, Australia.
Cancer Res. 2007 May 1;67(9):4482-90. doi: 10.1158/0008-5472.CAN-06-4244.
Cell line models of glucocorticoid resistance in childhood acute lymphoblastic leukemia (ALL) almost invariably exhibit altered glucocorticoid receptor (GR) function. However, these findings are incongruous with those using specimens derived directly from leukemia patients, in which GR alterations are rarely found. Consequently, mechanisms of glucocorticoid resistance in the clinical setting remain largely unresolved. We present a novel paradigm of glucocorticoid resistance in childhood ALL, in which patient biopsies have been directly established as continuous xenografts in immune-deficient mice, without prior in vitro culture. We show that the GRs from six highly dexamethasone-resistant xenografts (in vitro IC(50) >10 micromol/L) exhibit no defects in ligand-induced nuclear translocation and binding to a consensus glucocorticoid response element (GRE). This finding contrasts with five commonly used leukemia cell lines, all of which exhibited defective GRE binding. Moreover, whereas the GRs of dexamethasone-resistant xenografts were transcriptionally active, as assessed by the ability to induce the glucocorticoid-induced leucine zipper (GILZ) gene, resistance was associated with failure to induce the bim gene, which encodes a proapoptotic BH3-only protein. Furthermore, the receptor tyrosine kinase inhibitor, SU11657, completely reversed dexamethasone resistance in a xenograft expressing functional GR, indicating that pharmacologic reversal of glucocorticoid resistance in childhood ALL is achievable.
儿童急性淋巴细胞白血病（ALL）中糖皮质激素抵抗的细胞系模型几乎总是表现出糖皮质激素受体（GR）功能改变。然而，这些发现与直接来自白血病患者的标本的研究结果不一致，在后者中很少发现GR改变。因此，临床环境中糖皮质激素抵抗的机制在很大程度上仍未得到解决。我们提出了一种儿童ALL中糖皮质激素抵抗的新范式，其中患者活检标本已直接在免疫缺陷小鼠中建立为连续异种移植，无需事先进行体外培养。我们发现，来自六个对地塞米松高度耐药的异种移植（体外IC(50)>10 μmol/L）的GR在配体诱导的核转位以及与共有糖皮质激素反应元件（GRE）结合方面没有缺陷。这一发现与五种常用的白血病细胞系形成对比，所有这些细胞系均表现出GRE结合缺陷。此外，通过诱导糖皮质激素诱导的亮氨酸拉链（GILZ）基因的能力评估，地塞米松耐药异种移植的GR具有转录活性，而耐药与未能诱导bim基因有关，该基因编码一种仅含BH3结构域的促凋亡蛋白。此外，受体酪氨酸激酶抑制剂SU11657完全逆转了表达功能性GR的异种移植中的地塞米松耐药性，表明儿童ALL中糖皮质激素耐药性的药物逆转是可以实现的。
