[HTML][HTML] CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

Y Chen, R Jacamo, M Konopleva… - The Journal of …, 2013 - Am Soc Clin Investig
Y Chen, R Jacamo, M Konopleva, R Garzon, C Croce, M Andreeff
The Journal of clinical investigation, 2013Am Soc Clin Investig
We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor
1α/CXCR4 (SDF-1α/CXCR4) axis to overcome chemoresistance of AML cells. Microarray
analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1α–
mediated CXCR4 activation and increased by CXCR4 inhibition. 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 …
We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1α/CXCR4 (SDF-1α/CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1α–mediated CXCR4 activation and increased by CXCR4 inhibition. 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-1α/CXCR4 signaling and let-7a, as YY1 was upregulated by SDF-1α 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.
The Journal of Clinical Investigation