RRC ID 41909
著者 Minami Y, Yamamoto K, Kiyoi H, Ueda R, Saito H, Naoe T.
タイトル Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia.
ジャーナル Blood
Abstract An internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 (FLT3/ITD) has been found in 20% of patients with acute myeloid leukemia (AML) and is correlated with leukocytosis and a poor prognosis. Here, we compared the antiapoptotic effects of wild-type FLT3 (WtFLT3) and FLT3/ITD in terms of the regulation of Bcl-2 family members. In a murine myeloid cell line, 32D, interleukin-3 (IL-3) deprivation induced apoptosis following the down-regulation of Bcl-XL and the dephosphorylation of Bad. However, the expression levels of Bcl-2, Bax, Bak, and Mcl-1 were unchanged. In WtFLT3-transfected 32D (WtFLT3-32D) cells, FLT3 ligand (FL) stimulation did not restore the down-regulation of Bcl-XL but maintained the phosphorylation of Bad. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, dephosphorylated Bad and induced apoptosis in WtFLT3-32D cells stimulated with FL. Induction of nonphosphorylated Bad induced remarkable apoptosis. These findings suggest that the FL stimulation is associated with antiapoptosis through Bad phosphorylation. On the other hand, FLT3/ITD-transfected 32D (FLT3/ITD-32D) cells survived in an IL-3-or FL-deprived state. Furthermore, the dephosphorylation of Bad using LY294002 and PD98059 was insufficient for apoptosis, and the down-regulation of Bcl-XL using antisense treatment was needed to induce apoptosis. FLT3 kinase inhibitor, AG1296, alone not only dephosphorylated Bad but also down-regulated Bcl-XL, leading FLT3/ITD-32D cells into apoptosis. These findings suggest that the antiapoptotic pathways from FLT3/ITD are more divergent than those from WtFLT3 and may represent targets for drug discovery with the potential of inducing selective cell death of human leukemia cells.
巻・号 102(8)
ページ 2969-75
公開日 2003-10-15
DOI 10.1182/blood-2002-12-3813
PII S0006-4971(20)50449-7
PMID 12842996
MeSH Apoptosis* Cell Division Cell Line Chromones / pharmacology Dose-Response Relationship, Drug Down-Regulation Enzyme Inhibitors / pharmacology Flavonoids / pharmacology Humans Immunoblotting Leukemia / genetics* Leukemia / pathology* Ligands Membrane Proteins / genetics* Morpholines / pharmacology Mutation* Oligonucleotides, Antisense / pharmacology Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Precipitin Tests Prognosis Proto-Oncogene Proteins c-bcl-2 / metabolism Signal Transduction Time Factors Transfection bcl-X Protein
IF 17.794
引用数 67
WOS 分野 HEMATOLOGY
リソース情報
ヒト・動物細胞 32D(RCB1145)