VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease
VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease
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DOI：
10.1182/blood-2005-06-2530
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发表时间：
2006-02-15
期刊：
影响因子：
20.3
通讯作者：
Dias, S
中科院分区：
文献类型：
--
作者：
Fragoso, R;Pereira, T;Dias, S
对于急性白血病患者来说，持续性循环白血病细胞的存在或植入髓外组织是一个不良的预后因素。然而，对白血病细胞退出骨髓微环境的调控机制却知之甚少。我们发现，血管内皮生长因子受体1(flt-1)调节急性白血病在骨髓中的分布，沿着血管内皮生长因子和PIGF梯度，调节白血病存活和进入外周循环。Flt-1在急性淋巴细胞白血病(ALL)细胞上的激活在体外可导致细胞迁移和增殖，而在体内，非肥胖型糖尿病重度联合免疫缺陷(NOD-SCID)受者骨髓中Flt-1过表达的细胞聚集在骨痂中，并在接种后2周在循环中检测到Flt-1过表达的细胞。反过来，Flt-1中和影响白血病的定位(目前在骨髓骨干)，增加白血病细胞凋亡，并阻碍所有细胞的退出，延长接种小鼠的生存时间。我们进一步证明，Flt-1诱导的细胞迁移涉及肌动蛋白聚合和脂筏形成。综上所述，我们表明Flt-1调节所有细胞的BM定位，决定它们的存活和进入循环，并最终决定接种受体的存活。针对急性白血病亚群的Flt-1可以延缓髓外疾病的发生，这在联合治疗环境中可能是有利的。
The presence of persistent circulating leukemia cells, or engrafted into extramedullary tissues, is a bad prognostic factor for patients with acute leukemia. However, little is known about the mechanisms that regulate the exit of leukemia cells from the bone marrow (BM) microenvironment. We reveal that vascular endothelial growth factor receptor 1 (FLT-1) modulates acute leukemia distribution within the BM, along VEGF and PIGF gradients, regulating leukemia survival and exit into the peripheral circulation. FLT-1 activation on acute lymphoblastic leukemia (ALL) cells results in cell migration and proliferation in vitro, whereas in vivo FLT-1-overexpressing cells accumulate in the BM epiphysis of nonobese diabetic-severe combined immunodeficient (NOD-SCID) recipients and are detected in circulation 2 weeks after inoculation. In turn, FLT-1 neutralization affects leukemia localization (now in the BM diaphysis), increases leukemia apoptosis, and impedes the exit of ALL cells, prolonging the survival of inoculated mice. We demonstrate further that FLT-1-induced cell migration involves actin polymerization and lipid raft formation. Taken together, we show that FLT-1 regulates the BM localization of ALL cells, determining their survival and exit into the circulation and ultimately the survival of inoculated recipients. FLT-1 targeting on subsets of acute leukemias may delay the onset of extramedullary disease, which may be advantageous in combinatorial therapeutic settings.