title: Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia.
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.
authors.affiliation: 1 Signal Transduction Laboratory, Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Anna
authors.initials: A
authors.lastname: Chorzalska
authors.affiliation: 1 Signal Transduction Laboratory, Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Javier Flores
authors.initials: JF
authors.lastname: Kim
authors.affiliation: 2 Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Karim
authors.initials: K
authors.lastname: Roder
authors.affiliation: 1 Signal Transduction Laboratory, Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tepper
authors.affiliation: 3 Division of Biology and Medicine, Brown University , Center for Cancer Research and Development Proteomics Core Facility, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Nagib
authors.initials: N
authors.lastname: Ahsan
authors.affiliation: 4 Division of Biostatistics and Bioinformatics Division, Yenepoya Research Center, Yenepoya University , Mangalore, India .
authors.forename: R Shyama Prasad
authors.initials: RSP
authors.lastname: Rao
authors.affiliation: 5 Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Olszewski
authors.affiliation: 6 Department of Biostatistics, Yale School of Public Health , New Haven, Connecticut.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: 2 Division of Cardiology, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Terentyev
authors.affiliation: 7 Flow Cytometry and Cell Sorting Core Facility, Roger Williams Medical Center , Providence, Rhode Island.
authors.forename: John
authors.initials: J
authors.lastname: Morgan
authors.affiliation: 8 Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Diana O
authors.initials: DO
authors.lastname: Treaba
authors.affiliation: 9 Cardiovascular Laboratory, Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine , Providence, Rhode Island.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
authors.affiliation: 5 Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.|10 Department of Orthopedics, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Olin
authors.initials: O
authors.lastname: Liang
authors.affiliation: 11 Department of Pediatrics, Brown University , Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gruppuso
authors.affiliation: 1 Signal Transduction Laboratory, Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University , Providence, Rhode Island.
authors.forename: Patrycja M
authors.initials: PM
authors.lastname: Dubielecka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D000090683:Hippo Signaling Pathway; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D047428:Protein Kinase Inhibitors; C472575:SALL4 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C094990:adhesion receptor; D000068877:Imatinib Mesylate; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; YAP; chemoresistance; imatinib mesylate; leukemic stem cells; tyrosine kinase inhibitor