Effect of FLT3 inhibition on normal hematopoietic progenitor cells.
Ligand-mediated activation of the FMS-like tyrosine kinase-3 (FLT3) receptor is important for normal proliferation of primitive hematopoietic cells. FLT3 expression in the bone marrow is restricted to CD34(+) cells and a subset of dendritic precursors. FLT3, as a member of the type III RTK subfamily, is closely related to c-kit, c-FMS, and PDGFalpha/beta and is an unspecific target of tyrosine kinase inhibitors, such as imatinib. Activating mutations of FLT3 play an important role in leukemogenesis and their presence is associated with poor prognosis in acute myeloid leukemia (AML). Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is a promising therapeutic option in the treatment of AML patients. CEP-701 (Lestaurtinib), an indocarbazole derivate, is an FLT3 tyrosine kinase inhibitor. In this study, we investigated the effect of FLT3 kinase inhibition on normal hematopoietic stem and progenitor cells in vitro. FLT3 inhibition in normal CD34(+) cells resulted in a dose-dependent inhibitory effect in cell expansion. In contrast, progenitor cell function remained nearly unaffected. Blocking the FLT3 ligand by a neutralizing antibody partially restored the effects of FLT3 inhibition. These findings might explain hematotoxicity of tyrosine kinase inhibitors such as imatinib.
Weisel
Katja C
KC
University of Tübingen, Medical Center, Department of Hematology, Oncology and Immunology, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. katja.weisel@med.uni-tuebingen.de
Yildirim
Sedat
S
Schweikle
Eric
E
Kanz
Lothar
L
Möhle
Robert
R
D018952:Antigens, CD34 / Q000096:biosynthesis / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016130:Immunophenotyping; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008954:Models, Biological; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018952:Antigens, CD34; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005663:Furans; D007211:Indoles; D008024:Ligands; D013778:Tetrazolium Salts; D013844:Thiazoles; C119379:lestaurtinib; D051941:fms-Like Tyrosine Kinase 3; C022616:thiazolyl blue