PDF(Pubmed)
Abstract：
Acute myeloid leukemia (AML) is characterized by the abnormal proliferation and differentiation arrest of myeloid progenitor cells. The clinical treatment of AML remains challenging. Promoting AML cell differentiation is a valid strategy, but effective differentiation drugs are lacking for most types of AML. In this study, we generated Tg(drl:hoxa9) zebrafish, in which hoxa9 overexpression was driven in hematopoietic cells and myeloid differentiation arrest was exhibited. Using Tg(drl:hoxa9) embryos, we performed chemical screening and identified four FDA-approved drugs, ethacrynic acid, khellin, oxcarbazepine, and alendronate, that efficiently restored myeloid differentiation. The four drugs also induced AML cell differentiation, with ethacrynic acid being the most effective. By an RNA-seq analysis, we found that during differentiation, ethacrynic acid activated the IL-17 and MAPK signaling pathways, which are known to promote granulopoiesis. Furthermore, we found that ethacrynic acid enhanced all-trans retinoic acid (ATRA)-induced differentiation, and both types of signaling converged on the IL-17/MAPK pathways. Inhibiting the IL-17/MAPK pathways impaired ethacrynic acid and ATRA-induced differentiation. In addition, we showed that ethacrynic acid is less toxic to embryogenesis and less disruptive to normal hematopoiesis than ATRA. Thus, the combination of ethacrynic acid and ATRA may have broader clinical applications. In conclusion, through zebrafish-aided screening, our study identified four drugs that can be repurposed to induce AML differentiation, thus providing new agents for AML therapy.
摘要：
急性髓系白血病(AML)以髓系祖细胞的异常增殖和分化停滞为特征。AML的临床治疗仍然具有挑战性。促进AML细胞分化是一种有效的策略，但大多数类型的AML缺乏有效的分化药物.在这项研究中,我们产生了Tg(drl:hoxa9)斑马鱼，其中在造血细胞中驱动hoxa9过表达,并表现出髓样分化停滞.使用Tg(drl:hoxa9)胚胎，我们进行了化学筛选，确定了四种FDA批准的药物，乙丙炔酸,Khellin,奥卡西平,和阿仑膦酸盐,有效恢复骨髓分化。这四种药物还能诱导AML细胞分化，依替尼酸是最有效的。通过RNA-seq分析,我们发现在分化过程中，乙烯丙炔酸激活IL-17和MAPK信号通路,已知促进粒细胞生成。此外，我们发现乙丙炔酸增强全反式维甲酸（ATRA）诱导的分化，两种类型的信号都集中在IL-17/MAPK通路上。抑制IL-17/MAPK途径会损害依那丙炔酸和ATRA诱导的分化。此外,我们发现,与ATRA相比,依替尼酸对胚胎发生的毒性较小,对正常造血的破坏也较小.因此，依替尼酸和ATRA的联合应用可能具有更广泛的临床应用。总之,通过斑马鱼辅助筛查，我们的研究确定了四种可用于诱导AML分化的药物，从而为AML治疗提供新的药物。
