Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells
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Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells. / Weisel, Katja C; Yildirim, Sedat; Schweikle, Eric; Kanz, Lothar; Möhle, Robert.
in: ANN HEMATOL, Jahrgang 88, Nr. 3, 03.2009, S. 203-11.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells
AU - Weisel, Katja C
AU - Yildirim, Sedat
AU - Schweikle, Eric
AU - Kanz, Lothar
AU - Möhle, Robert
PY - 2009/3
Y1 - 2009/3
N2 - FLT3 and its ligand (FL) are one of the regulators of normal hematopoiesis. Ligand-independent activation of FLT3 occurs in about 30% of acute myeloid leukemia cases and is one goal for selectively targeted therapies. However, the function of FLT3/FL in the regulation of non-malignant immature hematopoietic cells is poorly characterized. In order to elucidate the role of FLT3 in normal hematopoiesis, human adult CD34(+) hematopoietic progenitor cells were cultured in cytokine-supplemented liquid culture in the presence or absence of FLT3 inhibition by CEP-701 (lestaurtinib). Total cell number, lineage-committed, and primitive progenitors and apoptosis were assayed. FLT3 expression and FL secretion in various conditions were analyzed by fluorescent activated cell sorter and enzyme-linked immunosorbent assay. Effects of nonspecific targeting of FLT3 were evaluated with addition of imatinib (Gleevec) to cell cultures. It is demonstrated that FLT3 inhibition impaired cell and progenitor cell growth and increased the rate in apoptosis. Effects were observed independent of addition of FL. The dose-dependent growth inhibition was partially equalized by inhibiting FL with a neutralizing antibody. FLT3 inhibition resulted in markedly increased production of FL by cultured CD34(+) cells as well as upregulation of FLT3 expression. Imatinib mimicked effects of selective FLT3 inhibition. In conclusion, FLT3 and its ligand regulate proliferation of hematopoietic progenitor cells in an autocrine/paracrine manner Nonspecific inhibition of FLT3 may contribute to hematotoxicity caused by imatinib treatment.
AB - FLT3 and its ligand (FL) are one of the regulators of normal hematopoiesis. Ligand-independent activation of FLT3 occurs in about 30% of acute myeloid leukemia cases and is one goal for selectively targeted therapies. However, the function of FLT3/FL in the regulation of non-malignant immature hematopoietic cells is poorly characterized. In order to elucidate the role of FLT3 in normal hematopoiesis, human adult CD34(+) hematopoietic progenitor cells were cultured in cytokine-supplemented liquid culture in the presence or absence of FLT3 inhibition by CEP-701 (lestaurtinib). Total cell number, lineage-committed, and primitive progenitors and apoptosis were assayed. FLT3 expression and FL secretion in various conditions were analyzed by fluorescent activated cell sorter and enzyme-linked immunosorbent assay. Effects of nonspecific targeting of FLT3 were evaluated with addition of imatinib (Gleevec) to cell cultures. It is demonstrated that FLT3 inhibition impaired cell and progenitor cell growth and increased the rate in apoptosis. Effects were observed independent of addition of FL. The dose-dependent growth inhibition was partially equalized by inhibiting FL with a neutralizing antibody. FLT3 inhibition resulted in markedly increased production of FL by cultured CD34(+) cells as well as upregulation of FLT3 expression. Imatinib mimicked effects of selective FLT3 inhibition. In conclusion, FLT3 and its ligand regulate proliferation of hematopoietic progenitor cells in an autocrine/paracrine manner Nonspecific inhibition of FLT3 may contribute to hematotoxicity caused by imatinib treatment.
KW - Carbazoles
KW - Cell Proliferation
KW - Cells, Cultured
KW - Dose-Response Relationship, Drug
KW - Hematopoiesis
KW - Hematopoietic Stem Cells
KW - Humans
KW - Membrane Proteins
KW - fms-Like Tyrosine Kinase 3
KW - Comparative Study
KW - Journal Article
U2 - 10.1007/s00277-008-0605-6
DO - 10.1007/s00277-008-0605-6
M3 - SCORING: Journal article
C2 - 18797870
VL - 88
SP - 203
EP - 211
JO - ANN HEMATOL
JF - ANN HEMATOL
SN - 0939-5555
IS - 3
ER -