Effect of FLT3 inhibition on normal hematopoietic progenitor cells
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Effect of FLT3 inhibition on normal hematopoietic progenitor cells. / Weisel, Katja C; Yildirim, Sedat; Schweikle, Eric; Kanz, Lothar; Möhle, Robert.
in: ANN NY ACAD SCI, Jahrgang 1106, 06.2007, S. 190-6.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung
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TY - JOUR
T1 - Effect of FLT3 inhibition on normal hematopoietic progenitor cells
AU - Weisel, Katja C
AU - Yildirim, Sedat
AU - Schweikle, Eric
AU - Kanz, Lothar
AU - Möhle, Robert
PY - 2007/6
Y1 - 2007/6
N2 - 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.
AB - 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.
KW - Antigens, CD34
KW - Carbazoles
KW - Dose-Response Relationship, Drug
KW - Enzyme Inhibitors
KW - Hematopoietic Stem Cells
KW - Humans
KW - Immunophenotyping
KW - Indoles
KW - Inhibitory Concentration 50
KW - Ligands
KW - Models, Biological
KW - Signal Transduction
KW - Tetrazolium Salts
KW - Thiazoles
KW - fms-Like Tyrosine Kinase 3
KW - Journal Article
U2 - 10.1196/annals.1392.020
DO - 10.1196/annals.1392.020
M3 - SCORING: Journal article
C2 - 17442779
VL - 1106
SP - 190
EP - 196
JO - ANN NY ACAD SCI
JF - ANN NY ACAD SCI
SN - 0077-8923
ER -