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

Anna Chorzalska, Javier Flores Kim, Karim Roder, Alexander Tepper, Nagib Ahsan, R. Shyama Prasad Rao, Adam J. Olszewski, Xiaoqing Yu, Dmitry Terentyev, John Morgan, DIana O. Treaba, Ting C. Zhao, Olin Liang, Philip A. Gruppuso, Patrycja M. Dubielecka

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)656-677
Number of pages22
JournalStem Cells and Development
Volume26
Issue number9
DOIs
StatePublished - 1 May 2017
Externally publishedYes

Keywords

  • Chemoresistance
  • Hippo pathway
  • Imatinib mesylate
  • Leukemic stem cells
  • Tyrosine kinase inhibitor
  • YAP

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