Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, ~30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or preexisting mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.

中文翻译：

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糖皮质激素受体表达的缺失介导了 T 细胞急性淋巴细胞白血病的体内地塞米松抵抗。

尽管临床使用了几十年，但对糖皮质激素抵抗的机制知之甚少。我们用单独的糖皮质激素地塞米松 (DEX) 和与泛 PI3 激酶抑制剂 GDC-0941 联合治疗原发性小鼠 T 谱系急性淋巴细胞白血病 (T-ALL)，并观察到 ​​GDC-0941 适度增强对 DEX 的强烈反应. 持续的体内治疗总是导致耐药克隆的生长，其中约 30% 的糖皮质激素受体 (GR) 蛋白表达显着降低。相似比例的复发性人类 T-ALL 也表现出低 GR 蛋白水平。编码 GR (Nr3c1) 的基因的从头或预先存在的突变发生在源自多个独立亲本白血病的复发克隆中。CRISPR/Cas9 基因编辑证实 GR 表达的丧失赋予 DEX 抗性。在体内将药物敏感性 T-ALL 暴露于 DEX 改变了多个基因的转录水平，并且这种反应在复发的 T-ALL 中减弱。这些数据表明 GR 蛋白表达降低是 T-ALL 中糖皮质激素抵抗的常见原因。