Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365

Exp Cell Res. 2018 Jan 15;362(2):386-393. doi: 10.1016/j.yexcr.2017.12.001. Epub 2017 Dec 6.

Abstract

Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells. Majority of patients can be effectively treated with tyrosine kinase inhibitors (TKIs) such as imatinib, but a portion of patients will develop drug resistance. Accumulated evidences have identified exosomes in cancer as promoters of tumor progression. Herein, we found that exosomes derived from imatinib resistant CML cells can be internalized into sensitive CML cells and confer drug-resistance traits. We also demonstrated a significant higher level of miR-365 in exosomes derived from drug-resistant CML cells compared with those from sensitive ones using microarray and qRT-PCR. The imatinib sensitive CML cells transfected with pre-miR-365 displayed lower chemosensitivity and apoptosis rate compared with controls. We further confirmed that exosomal transfer of miR-365 induced drug resistance by inhibiting expression of pro-apoptosis protein in sensitive CML cells. In conclusion, our study reveals that exosomes mediate a horizontal transfer of drug-resistant trait in chronic myeloid leukemia cell by delivering miR-365.

Keywords: Chemosensitivity; Chronic myeloid leukemia; Exosomes; MiR-365.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Autophagy / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Exosomes / drug effects
  • Exosomes / transplantation
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Imatinib Mesylate / adverse effects
  • Imatinib Mesylate / pharmacology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • MicroRNAs / genetics*
  • Protein Kinase Inhibitors / administration & dosage

Substances

  • MIRN365 microRNA, human
  • MicroRNAs
  • Protein Kinase Inhibitors
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl