CXCR4 Downregulation of let-7a Drives Chemoresistance in Acute Myeloid Leukemia

J Clin Invest. 2013 Jun;123(6):2395-407. doi: 10.1172/JCI66553. Epub 2013 May 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Chemokine CXCL12 / physiology
  • Cytarabine / pharmacology
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / physiology*
  • Signal Transduction
  • Transcriptome
  • Tumor Burden
  • Xenograft Model Antitumor Assays
  • YY1 Transcription Factor / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Antimetabolites, Antineoplastic
  • BCL2L1 protein, human
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • MicroRNAs
  • Receptors, CXCR4
  • YY1 Transcription Factor
  • YY1 protein, human
  • bcl-X Protein
  • mirnlet7 microRNA, human
  • Cytarabine