文章：

MicroRNA-146a和AMD3100，两种控制急性髓性白血病中CXCR4表达的方法

MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

原文发布日期：2011-06-24

DOI: 10.1038/bcj.2011.24

类型: Original Article

开放获取: 是

英文摘要：

CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies.

摘要翻译： 

CXCR4是急性髓系白血病（AML）中的一个不良预后标志物。因此，有必要开发抑制白血病中CXCR4表达的新方法。AMD3100是目前用于动员癌细胞的CXCR4抑制剂。CXCR4是microRNA（miR）-146a的靶点，这可能为抑制CXCR4表达提供新工具。我们随后研究了原发性AML中miR-146a对CXCR4的调控作用，发现在所有AML亚型中，miR-146a与CXCR4蛋白表达水平呈负相关。由于在M5型AML中观察到最低的miR-146a表达水平，我们分析了正常和白血病单核细胞中miR-146a对CXCR4表达的调控作用，结果表明调节性miR-146a/CXCR4通路在单核细胞生成过程中发挥作用，但在AML中失调。采用AMD3100处理和miR-146a过表达来抑制白血病细胞中的CXCR4。AMD3100处理诱导CXCR4蛋白表达降低，伴随miR-146a增加，并提高白血病原始细胞对细胞毒性药物的敏感性，而miR-146a过表达进一步增强了这种效应。总之，我们的数据表明，miR-146a和AMD3100通过不同机制下调CXCR4蛋白水平，抑制白血病细胞增殖，因此可与抗白血病药物联合使用，用于开发新的治疗策略。

原文链接：

MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias