Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells
Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells
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FLT3及其配体在正常造血祖细胞中的调控
DOI：
10.1007/s00277-008-0605-6
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发表时间：
2009
影响因子：
3.5
通讯作者：
R. Möhle
中科院分区：
文献类型：
--
作者：
K. Weisel;S. Yıldırım;Eric Schweikle;L. Kanz;R. Möhle
FLT 3及其配体（FL）是正常造血的调节因子之一。FLT 3的配体非依赖性激活发生在约30%的急性髓性白血病病例中，并且是选择性靶向治疗的一个目标。然而，FLT 3/FL在非恶性未成熟造血细胞的调节中的功能的特征很差。为了阐明FLT 3在正常造血中的作用，在存在或不存在CEP-701（来鲁替尼）抑制FLT 3的情况下，在补充有奎宁的液体培养物中培养人成人CD 34+造血祖细胞。分析总细胞数、谱系定型细胞、原始祖细胞和细胞凋亡。用荧光激活细胞分选仪和酶联免疫吸附试验分析不同条件下FLT 3的表达和FL的分泌。通过向细胞培养物中加入伊马替尼（Gleevec®）来评价非特异性靶向FLT 3的作用。FLT 3抑制受损细胞和祖细胞生长并增加凋亡率。观察到的效果独立的添加FL。剂量依赖性的生长抑制部分均衡抑制FL与中和抗体。FLT 3抑制导致培养的CD 34+细胞的FL产生显著增加以及FLT 3表达上调。伊马替尼模拟选择性FLT 3抑制的作用。总之，FLT 3及其配体以自分泌/旁分泌方式调节造血祖细胞的增殖，FLT 3的非特异性抑制可能导致伊马替尼治疗引起的血液毒性。
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.
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影响因子：
20.3
作者：
Zheng, R;Levis, M;Small, D
通讯作者：
Small, D
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作者：
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通讯作者：
Deeg,HJ
影响因子：
20.3
作者：
Smith, BD;Levis, M;Small, D
通讯作者：
Small, D
影响因子：
20.3
作者：
Levis, M;Allebach, J;Small, D
通讯作者：
Small, D
在离体逆转录病毒介导的转导后，FLT3 配体保留了免疫缺陷小鼠中人类 CD34 祖细胞维持长期造血的能力。
影响因子：
20.3
作者：
Dao,MA;Hannum,CH;Kohn,DB;Nolta,JA
通讯作者：
Nolta,JA