Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway
Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway
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DOI：
10.1158/1535-7163.mct-11-0503
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发表时间：
2012-01-01
影响因子：
5.7
通讯作者：
Lock, Richard B.
中科院分区：
文献类型：
--
作者：
Markovic, Ana;MacKenzie, Karen L.;Lock, Richard B.
人白血病细胞分泌VEGF，其可以在骨髓微环境中以旁分泌方式起作用以促进白血病细胞存活和增殖。FLT-3受体酪氨酸激酶在调节正常造血中起重要作用，但其在急性白血病中通过突变的组成性激活通常与不良结局相关。本研究的目的是研究急性白血病中FLT-3和VEGF信号通路之间的相互作用，使用细胞系和免疫缺陷小鼠中直接患者外植体扩增后的儿科急性淋巴细胞白血病细胞的离体培养物。不同的异种移植物系表现出可变的细胞表面FLT-3表达，以及基础和FLT-3配体诱导的VEGF分泌，而表达组成型活性FLT-3的MV 4; 11细胞系分泌高水平的VEGF。FLT-3抑制剂SU 11657显著降低了6个异种移植物系中的3个和MV 4; 11细胞中的VEGF分泌，并抑制了FLT-3酪氨酸磷酸化。此外，异种移植细胞暴露于FLT-3阻断抗体D43也将VEGF分泌降低至基础水平并降低FLT-3酪氨酸磷酸化。在下游信号方面，SU 11657和D43均引起细胞外信号调节激酶1/2的去磷酸化，而AKT或STAT 5磷酸化没有变化。最后，通过短干扰RNA部分敲低FLT-3表达也导致VEGF分泌的抑制。这些结果表明，FLT-3信号在VEGF分泌的调节中起着重要作用，并且FLT-3/VEGF途径的抑制可能会破坏白血病细胞和骨髓微环境之间的旁分泌信号。Mol Cancer Ther; 11（1）; 183-93. (C)2011年AACR。
Human leukemia cells secrete VEGF, which can act in a paracrine manner within the bone marrow microenvironment to promote leukemia cell survival and proliferation. The FLT-3 receptor tyrosine kinase plays an essential role in regulating normal hematopoiesis, but its constitutive activation via mutation in acute leukemias is generally associated with poor outcome. The aim of this study was to investigate interactions between the FLT-3 and VEGF signaling pathways in acute leukemia using cell lines and ex vivo cultures of pediatric acute lymphoblastic leukemia cells following expansion of direct patient explants in immunodeficient mice. Different xenograft lines exhibited variable cell surface FLT-3 expression, as well as basal and FLT-3 ligand-induced VEGF secretion, whereas the MV4; 11 cell line, which expresses constitutively active FLT-3, secreted high levels of VEGF. The FLT-3 inhibitor, SU11657, significantly reduced VEGF secretion in three of six xenograft lines and MV4; 11 cells, in conjunction with inhibition of FLT-3 tyrosine phosphorylation. Moreover, exposure of xenograft cells to the FLT-3-blocking antibody, D43, also reduced VEGF secretion to basal levels and decreased FLT-3 tyrosine phosphorylation. In terms of downstream signaling, SU11657 and D43 both caused dephosphorylation of extracellular signal-regulated kinase 1/2, with no changes in AKT or STAT5 phosphorylation. Finally, partial knockdown of FLT-3 expression by short interfering RNA also resulted in inhibition of VEGF secretion. These results indicate that FLT-3 signaling plays a central role in the regulation of VEGF secretion and that inhibition of the FLT-3/VEGF pathway may disrupt paracrine signaling between leukemia cells and the bone marrow microenvironment. Mol Cancer Ther; 11(1); 183-93. (C) 2011 AACR.