Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia

Stem Cells Dev. 2017 May 1;26(9):656-677. doi: 10.1089/scd.2016.0262. Epub 2017 Feb 27.


Despite the success of tyrosine kinase inhibitor (TKI) therapy in chronic myelogenous leukemia (CML), leukemic stem/progenitor cells remain detectable even in the state of deep molecular remission. Mechanisms that allow them to persist despite continued kinase inhibition remain unclear. We have previously shown that prolonged exposure to imatinib mesylate (IM) results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high IM. To characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomics, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to IM. Those cells demonstrated upregulation of pluripotency markers (SOX2, SALL4) and adhesion receptors (CD44, VLA-4, CXCR4), as well as downregulation of Hippo signaling and upregulation of transcription coactivator YAP. Furthermore, inhibition of miR-181a using a microRNA sponge inhibitor resulted in decreased transcription of SOX2 and SALL4, decreased activation of YAP, and increased sensitivity to IM. Our findings indicate that long-term exposure to IM results in dysregulation of stem cell renewal-regulatory Hippo/YAP signaling, acquisition of expression of stem cell markers and that experimental interference with YAP activity may help to restore chemosensitivity to TKI.

Keywords: Hippo pathway; YAP; chemoresistance; imatinib mesylate; leukemic stem cells; tyrosine kinase inhibitor.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Down-Regulation / drug effects*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Leukemic / drug effects
  • Hippo Signaling Pathway
  • Humans
  • Imatinib Mesylate / pharmacology*
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • MicroRNAs / genetics
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Platelet Glycoprotein GPIb-IX Complex / genetics
  • Platelet Glycoprotein GPIb-IX Complex / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • MIrn181 microRNA, human
  • MicroRNAs
  • Phosphoproteins
  • Platelet Glycoprotein GPIb-IX Complex
  • Protein Kinase Inhibitors
  • SALL4 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • adhesion receptor
  • Imatinib Mesylate
  • Protein Serine-Threonine Kinases