title: Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling.
abstract: Tyrosine kinase inhibitors (TKIs) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSCs), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSCs, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSCs from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSCs) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony-forming ability and engraftment potential in immunodeficient mice. We found that the N-cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-cadherin-mediated adhesion to MSCs was associated with increased cytoplasmic N-cadherin-β-catenin complex formation as well as enhanced β-catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated β-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-cadherin and the Wnt-β-catenin pathway in protecting CML LSCs during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSCs to TKI treatment and suggest new targets for treatment designed to eradicate residual LSCs in CML patients.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Duarte, CA 91010, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Tinisha
authors.initials: T
authors.lastname: McDonald
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Leonard
authors.initials: L
authors.lastname: Shultz
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051176:beta Catenin; D016044:Fusion Proteins, bcr-abl