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Stem Cells Dev. 2017 Jan 19. doi: 10.1089/scd.2016.0262. [Epub ahead of print]

Long-term exposure to imatinib mesylate downregulates Hippo pathway and activates YAP in a model of chronic myelogenous leukemia.

Author information

1
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; anna_chorzalska@brown.edu.
2
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; javier_flores_kim@alumni.brown.edu.
3
Division of Cardiology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; karim.roder@lifespan.org.
4
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; alexander_tepper@brown.edu.
5
Division of Biology and Medicine, Brown University, COBRE CCRD Proteomics Core Facility. Rhode Island Hospital, Providence, Rhode Island, United States ; nagib_ahsan@brown.edu.
6
Division of Biostatistics and Bioinformatics Division, Yenepoya Research Center, Yenepoya University, Mangalore, India ; drrsprao@gmail.com.
7
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; adam_olszewski@brown.edu.
8
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, United States ; xiaoqing.yu@yale.edu.
9
Division of Cardiology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; dmitry_terentyev@brown.edu.
10
Flow Cytometry and Cell Sorting Core Facility, Roger Williams Medical Center, Providence, Rhode Island, United States ; jmorgan@chartercare.org.
11
Department of Pathology and Laboratory Medicine at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States ; dtreaba@lifespan.org.
12
Cardiovascular Lab, Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island, United States ; tzhao@chartercare.org.
13
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Providence, Rhode Island, United States.
14
Division of Rheumatology, Department of Orthopedics, Warren Alpert Medical School of Brown University ; olin_liang@brown.edu.
15
10 Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, Rhode Island, United States ; philip_gruppuso@brown.edu.
16
Division of Hematology/Oncology at Rhode Island Hospital and Warren Alpert Medical School at Brown University, Medicine , One Hoppin street , Providence, Rhode Island, United States , 02903 ; Patrycja_Dubielecka-Szczerba@brown.edu.

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 results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high imatinib mesylate. In order to characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomic, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to imatinib mesylate. 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 co-activator 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 imatinib mesylate. Our findings indicate that long-term exposure to imatinib mesylate 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.

PMID:
28103766
DOI:
10.1089/scd.2016.0262
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