title: Dasatinib promotes the activation of quiescent hematopoietic stem cells in mice.
abstract: Dasatinib is an orally available broad-spectrum tyrosine kinase inhibitor that is widely used to treat chronic myeloid leukemia. It is also in clinical trials for the treatment of other malignancies, including solid tumors. Despite its wide use, little is known of its effects on normal hematopoietic stem and progenitor cells. Here, we study wild-type mice dosed with dasatinib and find that it causes the transient induction of proliferation of quiescent hematopoietic stem cells (HSCs). This finding was unexpected given the ability of dasatinib to inhibit c-Kit signaling and promote cell cycle arrest in many cell types. The transient induction of HSC proliferation in dasatinib-dosed mice coincided with a marked induction in the expression of Sca-1 and phospho-S6. Also evident at this time was a rapid but transient loss of lineage-committed hematopoietic progenitors that express high levels of c-Kit and the induction of stem cell factor in the serum. These findings suggest that activation of quiescent HSCs is part of a rapid rescue response that restores hematopoietic progenitors to pretreatment levels. This restoration coincides with HSCs returning to quiescence, and the expression of Sca-1 and phospho-S6 reverting to pre-treatment levels, even though dasatinib dosing is maintained. These data suggest that equilibrium is reached between the opposing forces of dasatinib and hematopoietic growth factors. The transient induction of HSC proliferation provided a window of opportunity whereby these cells became sensitive to killing by the cytotoxic drug 5-fluorouracil.
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Duyvestyn
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Taylor
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Dagger
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia. Electronic address: wally.langdon@uwa.edu.au.
authors.forename: Wallace Y
authors.initials: WY
authors.lastname: Langdon
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib / Q000494:pharmacology*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000097:blood / Q000378:metabolism; D013997:Time Factors
chemical_list: D000950:Antigens, Ly; D000963:Antimetabolites; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib; D005472:Fluorouracil