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

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

Author information

1
1 Signal Transduction Laboratory, Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
2
2 Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
3
3 Division of Biology and Medicine, Brown University , Center for Cancer Research and Development Proteomics Core Facility, Rhode Island Hospital, Providence, Rhode Island.
4
4 Division of Biostatistics and Bioinformatics Division, Yenepoya Research Center, Yenepoya University , Mangalore, India .
5
5 Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
6
6 Department of Biostatistics, Yale School of Public Health , New Haven, Connecticut.
7
7 Flow Cytometry and Cell Sorting Core Facility, Roger Williams Medical Center , Providence, Rhode Island.
8
8 Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
9
9 Cardiovascular Laboratory, Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine , Providence, Rhode Island.
10
10 Department of Orthopedics, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
11
11 Department of Pediatrics, Brown University , Rhode Island Hospital, Providence, Rhode Island.

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.

KEYWORDS:

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

PMID:
28103766
PMCID:
PMC5421616
[Available on 2018-05-01]
DOI:
10.1089/scd.2016.0262
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