Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers
Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers
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DOI：
10.1038/sj.leu.2401729
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发表时间：
2000-05-01
期刊：
影响因子：
11.4
通讯作者：
Gottlieb, DJ
中科院分区：
文献类型：
--
作者：
Bradstock, KF;Makrynikola, V;Gottlieb, DJ
急性淋巴细胞白血病（ALL）原始细胞在体外利用β1整合素VLA - 4和VL - 5作为黏附分子迁移到骨髓成纤维细胞（BMF）层。然而，尚不清楚这是一个由特定趋化分子介导的选择性过程，还是仅仅反映了早期B细胞前体的高度运动性。我们使用一种Transwell培养系统进一步对这一过程进行了研究，该系统中两个小室由直径为8μm的微孔膜隔开，白血病细胞可穿过此膜移动。当在膜的上表面培养一层BMF时，与人前B型ALL细胞系NALM - 6向无BMF层的对照膜下室的迁移相比，其迁移率降低了84.1%。通过超微结构证实了白血病细胞在BMF层下的定位，这表明白血病细胞的迁移可能是由BMF分泌的趋化因子所引导。接下来研究了趋化因子基质细胞衍生因子 - 1（SDF - 1）在这一过程中的作用。结果显示BMF表达SDF - 1的mRNA。在下室中加入100ng/ml的SDF - 1使NALM - 6穿过膜的迁移增加了2.2倍，并且还使NALM - 6穿过BMF层进入下室的移动增加了1.4 - 6.1倍。通过流式细胞术在分析的所有10例前体B型ALL病例以及NALM - 6、KM - 3和REH细胞系上证实了SDF - 1的受体CXCR4。一种针对CXCR4的抑制性抗体能够将NALM - 6细胞迁移到塑料培养板上生长的BMF单层的能力阻断51%，在9例ALL中阻断8 - 40%，并且部分抑制白血病细胞沿着SDF - 1浓度梯度穿过BMF层的迁移。这些结果证实，前体B型ALL细胞在体外选择性地定位于骨髓基质内，并且这一过程部分是由于基质趋化因子SDF - 1与其在白血病细胞上的受体CXCR4结合。SDF - 1在影响前体B型ALL细胞在骨髓微环境中的定位方面可能很重要，骨髓微环境调节着它们的存活和增殖。
Acute lymphoblastic leukemia (ALL) blasts undergo migration into layers of bone marrow fibroblasts (BMF) in vitro, utilizing the beta 1 integrins VLA-4 and VL-5 as adhesion molecules. However, it has been unclear as to whether this is a selective process mediated by specific chemoattractant molecules, or simply a reflection of the highly motile nature of early B cell precursors. We further characterized this process using a transwell culture system, in which the two chambers were separated by an 8 mu m diameter microporous membrane, through which leukemic cells could move. When a BMF layer was grown on the upper surface of the membrane there was an 84.1% reduction in transmigration of the human pre-B ALL cell line NALM-6 into the lower chamber, compared to control membrane with no BMF layer. Localization of leukemic cells under the BMF layer was confirmed ultrastructurally, suggesting the possibility that the migration of leukemic cells was directed by a chemotactic agent secreted by BMF. The involvement of the chemokine stromal cell-derived factor-1 (SDF-1) in this process was next investigated. BMF were shown to express m-RNA for SDF-1. Addition of SDF-1 at 100 ng/ml into the lower chamber increased transmigration of NALM-6 across the membrane by 2.2-fold, and also induced a 1.4- to 6.1-fold increase in movement of NALM-6 through a BMF layer into the lower chamber. The receptor for SDF-1, CXCR4, was demonstrated by flow cytometry on all 10 cases of precursor-B ALL analyzed, as well as on NALM-6, KM-3 and REH lines. An inhibitory antibody to CXCR4 was able to block the migration of NALM-6 cells into BMF monolayers grown on plastic by 51%, and in nine cases of ALL by 8-40%, as well as partially inhibit transmigration of leukemic cells through BMF layers along an SDF-1 concentration gradient. These results confirm that precursor-B ALL cells selectively localize within bone marrow stroma in vitro, and that this process is partially due to the stromal chemokine SDF-1 binding to its receptor CXCR4 on leukemic cells. SDF-1 may be important in influencing the localization of precursor-B ALL cells in marrow microenvironmental inches which regulate their survival and proliferation.