Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia.,Leukemia

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Loss of glucocorticoid receptor expression mediates in vivo dexamethasone resistance in T-cell acute lymphoblastic leukemia.
Leukemia ( IF 12.8 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41375-020-0748-6
Anica M Wandler ₁ , Benjamin J Huang ₁ , Jeffrey W Craig ₂ , Kathryn Hayes ₁ , Hannah Yan ₁ , Lauren K Meyer ₁ , Alessandro Scacchetti ₃ , Gabriela Monsalve ₃ , Monique Dail ₄ , Qing Li ₅ , Jasmine C Wong ₁ , Olga Weinberg ₆ , Robert P Hasserjian ₇ , Scott C Kogan ₈ , Philip Jonsson _{9,

10} , Keith Yamamoto ₃ , Deepak Sampath ₄ , Joy Nakitandwe ₁₁ , James R Downing ₁₁ , Jinghui Zhang ₁₂ , Jon C Aster ₂ , Barry S Taylor _{9,

10,

13} , Kevin Shannon ₁

Affiliation

Department of Pediatrics, University of California, San Francisco, CA, USA.
Department of Pathology, Brigham & Women's Hospital, Boston, MA, USA.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
Department of Translational Oncology, Genentech Inc., South San Francisco, CA, USA.
Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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：

糖皮质激素受体表达的丧失介导 T 细胞急性淋巴细胞白血病体内地塞米松耐药。

尽管临床使用已有数十年，但人们对糖皮质激素耐药机制仍知之甚少。我们单独使用糖皮质激素地塞米松 (DEX) 以及与泛 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)，并观察到对 DEX 的强烈反应，GDC-0941 适度增强了这种反应。。连续的体内治疗总是会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。类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) 的基因中的从头突变或预先存在的突变发生在源自多个独立亲代白血病的复发克隆中。 CRISPR/Cas9 基因编辑证实，GR 表达缺失会导致 DEX 抗性。将药物敏感的 T-ALL 暴露于 DEX 体内会改变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 蛋白表达减少是 T-ALL 糖皮质激素耐药的常见原因。

更新日期：2020-02-18

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