title: Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling.
abstract: In chronic myelogenous leukemia (CML), oncogenic BCR-ABL1 activates the Wnt pathway, which is fundamental for leukemia stem cell (LSC) maintenance. Tyrosine kinase inhibitor (TKI) treatment reduces Wnt signaling in LSCs and often results in molecular remission of CML; however, LSCs persist long term despite BCR-ABL1 inhibition, ultimately causing disease relapse. We demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70 in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation. Combining TKIs with CD70 blockade effectively eliminated human CD34(+) CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, targeting TKI-induced expression of CD70 and compensatory Wnt signaling resulting from the CD70/CD27 interaction is a promising approach to overcoming treatment resistance in CML LSCs.
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Riether
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland. Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Schürch
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Flury
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hinterbrandner
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Linda
authors.initials: L
authors.lastname: Drück
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Huguenin
authors.affiliation: Experimental Hematology, Department of Clinical Research, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland. Department of Hematology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Baerlocher
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
authors.forename: Ramin
authors.initials: R
authors.lastname: Radpour
authors.affiliation: Tumor Immunology, Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland. Department of Medical Oncology, Inselspital, University Hospital and University of Bern, 3010 Bern, Switzerland. adrian.ochsenbein@insel.ch.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
mesh_terms: D000818:Animals; D053282:CD27 Ligand / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; D047428:Protein Kinase Inhibitors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D011505:Protein-Tyrosine Kinases