The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression

Leukemia. 2017 Nov;31(11):2336-2346. doi: 10.1038/leu.2017.82. Epub 2017 Mar 10.


CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cyclin D1 / metabolism*
  • Down-Regulation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • MicroRNAs / metabolism*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Peptides / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptors, CXCR4 / antagonists & inhibitors*


  • 4-fluorobenzoyl-TN-14003
  • CXCR4 protein, human
  • MIRN15 microRNA, human
  • MIRN16 microRNA, human
  • MicroRNAs
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, CXCR4
  • Cyclin D1
  • Extracellular Signal-Regulated MAP Kinases