Imatinib inhibits the in vitro development of the monocyte/macrophage lineage from normal human bone marrow progenitors

• Published in: Leukemia Vol. 17; no. 9; pp. 1713 - 1721
• Main Authors: Dewar, A L, Domaschenz, R M, Doherty, K V, Hughes, T P, Lyons, A B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2003; Nature Publishing; Nature Publishing Group
• Subjects: Antigens, CD34 - metabolism; Antineoplastic agents; Antineoplastic Agents - pharmacology; BCR-ABL protein; Benzamides; Binding sites; Biological and medical sciences; Bone marrow; Bone Marrow Cells - drug effects; c-Kit protein; Cancer Research; Cell Differentiation - drug effects; Cell Division - drug effects; Cell Lineage; Cells, Cultured; Chemotherapy; Colony-Forming Units Assay; Critical Care Medicine; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; Eosinophils - cytology; Eosinophils - drug effects; Fusion protein; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Growth factors; Hematology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Humans; Imatinib; Imatinib Mesylate; In Vitro Techniques; Inhibitor drugs; Intensive; Internal Medicine; Kinases; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - pharmacology; Macrophages; Macrophages - cytology; Macrophages - drug effects; Medical sciences; Medicine; Medicine & Public Health; Monocytes; Monocytes - cytology; Monocytes - drug effects; Neutrophils - cytology; Neutrophils - drug effects; Oncology; Osteoprogenitor cells; Pathogenesis; Pharmacology. Drug treatments; Piperazines - pharmacology; Platelet-derived growth factor; Progenitor cells; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - metabolism; Pyrimidines - pharmacology; Receptor, Macrophage Colony-Stimulating Factor - antagonists & inhibitors; Receptors; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Semisolids; spotlight; Stem cell factor; Stem cells; Tyrosine; monocyte/macrophage; imatinib; haemopoiesis; Antineoplastic agent; Human; Imatinib; Healthy subject; Monocyte; Enzyme; Transferases; Stem cell; Hematopoietic cell; Enzyme inhibitor; In vitro; Biological activity; Hematopoiesis; Bone marrow; Protein-tyrosine kinase; Macrophage
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403071

The antileukaemic tyrosine kinase inhibitor, imatinib, has been reported to inhibit specifically the growth of bcr-abl expressing CML progenitors at levels of 0.1–5.0  μ M , by blocking the ATP-binding site of the kinase domain of bcr-abl . Inhibition of the c-abl , platelet-derived growth factor receptor and stem cell factor receptor ( c-kit ) tyrosine kinases by imatinib has also been reported. Here, we demonstrate that imatinib significantly inhibits in vitro monocyte/macrophage development from normal bone marrow progenitors, while neutrophil and eosinophil development was less affected. Monocyte/macrophage inhibition was observed in semisolid agar and liquid cultures at concentrations of imatinib as low as 0.3  μ M . The maturation of monocytes into macrophages was also found to be impaired following treatment of cultures with 1.0  μ M imatinib. Imatinib blocked monocyte/macrophage development in cultures stimulated with and without M-CSF, suggesting that inhibition of the M-CSF receptor, c-fms , by imatinib was unlikely to be responsible. Imatinib may therefore have an inhibitory activity for other kinase(s) that play a role in monocyte/macrophage differentiation. This inhibition of normal monocyte/macrophage development was observed at concentrations of imatinib achievable pharmacologically, suggesting that imatinib or closely related derivatives may have potential for the treatment of diseases where monocytes/macrophages contribute to pathogenesis.