Effect of FLT3 inhibition on normal hematopoietic progenitor cells

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 -