文章：

白血病干细胞特征识别靶向急性髓系白血病的新型疗法

Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia

原文发布日期：2018-06-06

DOI: 10.1038/s41408-018-0087-2

类型: Article

开放获取: 是

英文摘要：

Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug–gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.

摘要翻译： 

急性髓系白血病（AML）的治疗涉及强效细胞毒性疗法，然而约70%的AML患者对初始治疗无效或最终复发。这种现象至少部分源于维持疾病存在的白血病干细胞（LSCs）具有化疗耐药特性，因此新型抗LSC疗法有望降低复发率并提高生存率。我们通过计算机模拟分析高预后价值的人类AML LSC基因表达特征，利用现有药物-基因相互作用数据集，筛选出可靶向LSC基因程序的候选化合物。通过排除会抑制造血干细胞（HSC）基因特征的化合物，最终获得151种抗LSC候选物质。采用新型体外LSC检测技术，我们对84种候选化合物进行多剂量筛选，最终确认14种能有效清除人类AML LSCs的药物。其中三大药物家族呈现多重靶向效果：抗组胺药（阿司咪唑和特非那定）、强心苷（毒毛旋花子苷原、地高辛和哇巴因）及糖皮质激素（布地奈德、卤倍他索和莫米松），这些药物在人类原代AML样本中均验证具有抗白血病活性。本研究证明，将干细胞基因表达特征的计算机模拟分析与体外筛选相结合，能有效识别靶向AML复发根源——耐药性LSC的新型化合物。

原文链接：

Leukemic stem cell signatures identify novel therapeutics targeting acute myeloid leukemia