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Type: Journal article
Title: Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib
Author: Dewar, A.
Cambareri, A.
Zannettino, A.
Boog, B.
Doherty, K.
Hughes, T.
Lyons, A.
Citation: Blood, 2005; 105(8):3127-3132
Publisher: Amer Soc Hematology
Issue Date: 2005
ISSN: 0006-4971
Statement of
Andrea L. Dewar, Antony C. Cambareri, Andrew C. W. Zannettino, Bernadette L. Miller, Kathleen V. Doherty, Timothy P. Hughes, and A. Bruce Lyons
Abstract: From the Division of Haematology, Hanson Institute, Institute of Medical and Veterinary Science; and the Australian Red Cross Blood Service, Adelaide, South Australia, Australia. Imatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl–expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)–binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF–induced proliferation of a cytokine–dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.
Keywords: Monocytes
Bone Marrow Cells
Receptor, Macrophage Colony-Stimulating Factor
Protein Kinase Inhibitors
Signal Transduction
Cell Division
Proto-Oncogene Proteins c-kit
In Vitro Techniques
Imatinib Mesylate
Description: Copyright © 2005 by American Society of Hematology
DOI: 10.1182/blood-2004-10-3967
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