文章：

药物介导的Fli-1抑制治疗白血病

Drug-mediated inhibition of Fli-1 for the treatment of leukemia

原文发布日期：2012-01-27

DOI: 10.1038/bcj.2011.52

类型: Original Article

开放获取: 是

英文摘要：

The Ets transcription factor, Fli-1 is activated in murine erythroleukemia and overexpressed in various human malignancies including Ewing's sarcoma, induced by the oncogenic fusion protein EWS/Fli-1. Recent studies by our group and others have demonstrated that Fli-1 plays a key role in tumorigenesis, and disrupting its oncogenic function may serve as a potential treatment option for malignancies associated with its overexpression. Herein, we describe the discovery of 30 anti-Fli-1 compounds, characterized into six functional groups. Treatment of murine and human leukemic cell lines with select compounds inhibits Fli-1 protein or mRNA expression, resulting in proliferation arrest and apoptosis. This anti-cancer effect was mediated, at least in part through direct inhibition of Fli-1 function, as anti-Fli-1 drug treatment inhibited Fli-1 DNA binding to target genes, such as SHIP-1 and gata-1, governing hematopoietic differentiation and proliferation. Furthermore, treatment with select Fli-1 inhibitors revealed a positive relationship between the loss of DNA-binding activity and Fli-1 phosphorylation. Accordingly, anti-Fli-1 drug treatment significantly inhibited leukemogenesis in a murine erythroleukemia model overexpressing Fli-1. This study demonstrates the ability of this drug-screening strategy to isolate effective anti-Fli-1 inhibitors and highlights their potential use for the treatment of malignancies overexpressing this oncogene.

摘要翻译： 

Ets 转录因子 Fli-1 在小鼠红白血病中被激活，并在包括由致癌融合蛋白 EWS/Fli-1 诱导的尤文肉瘤在内的多种人类恶性肿瘤中过表达。我们团队及其他团队的最新研究已证实，Fli-1 在肿瘤发生中起关键作用，阻断其致癌功能可能成为治疗其过表达相关恶性肿瘤的潜在选择。本文我们报道了 30 种抗 Fli-1 化合物的发现，它们被划分为六个功能组。用选定化合物处理小鼠和人类白血病细胞系可抑制 Fli-1 蛋白或 mRNA 表达，导致增殖停滞和凋亡。这种抗癌效应至少部分通过直接抑制 Fli-1 功能实现，因为抗 Fli-1 药物处理抑制了 Fli-1 与靶基因（如调控造血分化和增殖的 SHIP-1 和 gata-1）的 DNA 结合。此外，用选定 Fli-1 抑制剂处理发现，DNA 结合活性的丧失与 Fli-1 磷酸化之间存在正相关。相应地，抗 Fli-1 药物处理在过表达 Fli-1 的小鼠红白血病模型中显著抑制了白血病的发生。本研究证明了该药物筛选策略分离有效抗 Fli-1 抑制剂的能力，并突出了其用于治疗过表达这一癌基因恶性肿瘤的潜力。

原文链接：

Drug-mediated inhibition of Fli-1 for the treatment of leukemia