CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia
CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia
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DOI：
10.1172/jci66553
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发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Chen, Ye;Jacamo, Rodrigo;Andreeff, Michael
我们研究了 microRNA (miRNA) 在靶向基质衍生因子 1 α/CXCR4 (SDF-1 α/CXCR4) 轴以克服 AML 细胞化疗耐药性方面的作用。 OCI-AML3 细胞的微阵列分析显示，miRNA let-7a 因 SDF-1 α 介导的 CXCR4 激活而下调，并因 CXCR4 的激活而增加。AML 细胞系中 let-7a 的过表达与 c-Myc 和 BCL-XL 蛋白表达减少以及体外和体内化学敏感性增强相关。我们确定转录因子 Yin Yang 1 (YY1) 是 SDF-1 α/CXCR4 信号传导和 let-7a 之间的联系，因为 YY1 被 SDF-1 α 上调，并通过 CXCR4 拮抗剂治疗下调。 ChIP 测定证实了 YY1 与未处理的 let-7a DNA 片段的结合，并且用 YY1 shRNA 处理增加了 let-7a 表达。在原发性人类 AML 样本中，CXCR4 高表达与 let-7a 水平低相关。原代人 AML 细胞的异种移植物经过工程改造，过度表达 let-7a，表现出对阿糖胞苷的敏感性增强，从而大大延长了免疫缺陷小鼠的生存期。基于这些数据，我们提出 CXCR4 通过下调 let-7a 来促进 AML 细胞中 YY1 介导的 MYC 和 BCLXL 转录激活，从而诱导化疗耐药。
We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1 alpha/CXCR4 (SDF-1 alpha/CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1 alpha-mediated CXCR4 activation and increased by CXCR4 Overexpression of let-7a in AML cell lines was associated with decreased c-Myc and BCL-XL protein expression and enhanced chemosensitivity, both in vitro and in vivo. We identified the transcription factor Yin Yang 1 (YY1) as a link between SDF-1 alpha/CXCR4 signaling and let-7a, as YY1 was upregulated by SDF-1 alpha and downregulated by treatment with a CXCR4 antagonist. ChIP assay confirmed the binding of YY1 to unprocessed let-7a DNA fragments, and treatment with YY1 shRNA increased let-7a expression. In primary human AML samples, high CXCR4 expression was associated with low let-7a levels. Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine, resulting in greatly extended survival of immunodeficient mice. Based on these data, we propose that CXCR4 induces chemoresistance by downregulating let-7a to promote YY1-mediated transcriptional activation of MYC and BCLXL in AML cells.