Cancer Cell Biology Program, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
Exp Hematol. 2010 Sep;38(9):733-43. doi: 10.1016/j.exphem.2010.05.001. Epub 2010 May 12.
Infiltration of the central nervous system (CNS) by leukemia is a problematic disease manifestation of acute lymphoblastic leukemia (ALL). The mechanisms by which leukocytes interact with human brain-derived microvasculature endothelial cells (HBMEC) and enter the CNS are largely derived from models of inflammation. However, our data indicate that ALL cells do not elicit an inflammatory phenotype by HBMEC. Our current investigation focuses on the contribution of the unique coexpression of vascular endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1) by ALL in mediating leukemic cell interactions with HBMEC as an in vitro model of the blood-brain barrier.
Primary ALL and ALL cell lines were evaluated for VE-cadherin and PECAM-1 expression. Lentiviral-mediated transduction of VE-cadherin and PECAM-1 into REH cells and antibody neutralization of VE-cadherin and PECAM-1 in SUP-B15 cells was used to delineate the role of these two proteins in mediating ALL adhesion to, and migration through, HBMEC monolayers.
Although cell line models indicate that VE-cadherin and PECAM-1 expression is found on the surface Philadelphia chromosome-positive ALL, evaluation of primary ALL demonstrates that VE-cadherin and PECAM-1 are expressed independent of Philadelphia status. Expression of VE-cadherin and PECAM-1 by ALL enhanced the adhesion of ALL to HBMEC, while expression of PECAM-1 enhanced ALL adhesion to, and migration through, HBMEC.
Expression of VE-cadherin and PECAM-1 by ALL cells positions them to interact with HBMEC. By increasing our understanding of molecular mechanisms through which ALL cells gain entry into the CNS, new strategies may be designed to prevent leukemia cell entry into the CNS.
白血病浸润中枢神经系统（CNS）是急性淋巴细胞白血病（ALL）的一种严重疾病表现。白细胞与人类脑源性微血管内皮细胞（HBMEC）相互作用并进入中枢神经系统的机制主要来源于炎症模型。然而，我们的数据表明，ALL 细胞不会通过 HBMEC 引发炎症表型。我们目前的研究重点是 ALL 细胞独特的血管内皮（VE）-钙黏蛋白和血小板内皮细胞黏附分子-1（PECAM-1）共表达在介导白血病细胞与 HBMEC 相互作用中的作用，因为 HBMEC 是血脑屏障的体外模型。
评估原发性 ALL 和 ALL 细胞系中 VE-cadherin 和 PECAM-1 的表达。通过慢病毒介导将 VE-cadherin 和 PECAM-1 转导到 REH 细胞中，并在 SUP-B15 细胞中中和 VE-cadherin 和 PECAM-1 的抗体，用于阐明这两种蛋白在介导 ALL 黏附到和穿过 HBMEC 单层中的作用。
尽管细胞系模型表明，VE-cadherin 和 PECAM-1 在表面费城染色体阳性 ALL 上表达，但对原发性 ALL 的评估表明，VE-cadherin 和 PECAM-1 的表达独立于费城状态。ALL 表达 VE-cadherin 和 PECAM-1 增强了 ALL 与 HBMEC 的黏附，而 PECAM-1 的表达增强了 ALL 与 HBMEC 的黏附，并穿过 HBMEC。
ALL 细胞表达 VE-cadherin 和 PECAM-1 使它们能够与 HBMEC 相互作用。通过加深我们对 ALL 细胞进入中枢神经系统的分子机制的理解，可能会设计出新的策略来防止白血病细胞进入中枢神经系统。
