CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia
Ye Chen, Rodrigo Jacamo, Marina Konopleva, Ramiro Garzon, Carlo Croce, Michael Andreeff
Ye Chen, Rodrigo Jacamo, Marina Konopleva, Ramiro Garzon, Carlo Croce, Michael Andreeff
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Research Article Oncology

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

Abstract

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.

Authors

Ye Chen, Rodrigo Jacamo, Marina Konopleva, Ramiro Garzon, Carlo Croce, Michael Andreeff

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Figure 5

Molm13 cells with overexpression of let-7a are more sensitive to chemotherapy in vitro and in vivo.

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Molm13 cells with overexpression of let-7a are more sensitive to chemoth...
(A) Expression of let-7a in Molm13 cells was upregulated with POL6326 treatment and decreased with SDF-1α administration, as determined by qRT-PCR. (B) Molm13-luc-GFP-let-7a cells were established by lentiviral infection, which showed approximately 1.6-fold more let-7a compared with the scrambled control. (C) Molm13-luc-GFP-let-7a cells exhibited significantly higher sensitivity to Ara-C treatment in vitro. (D) Molm13-luc-GFP-let-7a and scrambled control cells were injected into NSG mice (n = 8), and the mice were treated with either PBS or Ara-C twice a week from day 7. Serial images of 3 representative mice on days 0, 10, 14, and 18 after D-luciferin injection are shown. (E) Bioluminescence imaging was quantified in terms of luminescent intensity. (F) Overall survival rate in each group was estimated by Kaplan-Meier method (*P < 0.05). (G) 3 representative mice per group were sacrificed on day 18, and tissues were fixed and sliced for immunohistochemistry staining with an anti-firefly antibody to specifically identify human leukemic cells. Analysis of spectral images further confirmed the significantly reduced leukemia burden in Ara-C–treated Molm13-luc-GFP-let-7a cells. Original magnification, ×20 (liver and spleen); ×4 (femur). *P < 0.05, **P < 0.01.