期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 6, 页码 2395-2407出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI66553
关键词
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资金
- NIH [AML P01 CA55164, CA016672, CA143805, CA049639, CA136411, CA100632]
- Paul and Mary Haas Chair in Genetics grant
- National Cancer Institute [1R01CA155056-01]
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.
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