Department of Hematology-Immunology, School of Medicine, Marmara University, Istanbul, Turkey.
Cytometry B Clin Cytom. 2011 Jan;80(1):1-7. doi: 10.1002/cyto.b.20553. Epub 2010 Aug 31.
B-chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of CD5(+) B lymphocytes. Decreased VLA-4 (Cd49d/CD29) and CD11a expression and defective adhesion in B-CLL have been previously shown, although there was no substantial data about its importance in immunobiology of B-CLL. The hepatocyte growth factor (HGF) receptor, c-met, plays a role in adhesion by acting on VLA-4. c-met and VLA-4 share crucial signaling molecules in cell survival. In this study, relationship between expressions of c-met and CD49d, CD11a, and additional common signaling molecules in B-CLL was investigated.
White blood cells from 24 patients with CLL were studied by flow cytometry and/or western blotting prior to and after culturing with recombinant HGF. HGF level from sera was measured with a bead-based flow cytometric assay.
c-metα and c-metβ were expressed on B-CLL cells, while no expression was observed on normal donor CD19+ cells. This increase was inversely correlated with decreased expression of adhesion molecules. Serum level of HGF in B-CLL was found to be increased. In vitro experiments showed that HGF supported survival in B-CLL cells supporting the possible function of HGF/c-met pathway in B-CLL. Furthermore, expressions of critical signaling molecules shared by both VLA-4 and HGF/c-met systems including Bcl-XL, Akt, PI3K, and phospho-bad(136) following HGF stimulations of B-CLL cells have been found to be increased.
Increased expression of c-met and HGF may bypass the importance of expression of critical adhesion molecules and support survival of B-CLL cells. c-met, being one of the surface tyrosine kinases, may serve as a target for future therapies in B-CLL meriting more attention.
B 慢性淋巴细胞白血病（B-CLL）的特征是 CD5(+)B 淋巴细胞的积累。先前已经表明，B-CLL 中存在 VLA-4（Cd49d/CD29）和 CD11a 表达降低以及黏附功能缺陷，尽管在其在 B-CLL 免疫生物学中的重要性方面没有实质性数据。肝细胞生长因子（HGF）受体 c-met 通过作用于 VLA-4 发挥黏附作用。c-met 和 VLA-4 在细胞存活中共享关键信号分子。在这项研究中，研究了 B-CLL 中 c-met 与 CD49d、CD11a 和其他共同信号分子表达之间的关系。
在使用重组 HGF 培养之前和之后，通过流式细胞术和/或 Western blot 研究了 24 例 CLL 患者的白细胞。使用基于珠的流式细胞术测定法测量血清中 HGF 的水平。
c-metα 和 c-metβ 在 B-CLL 细胞上表达，而在正常供体 CD19+细胞上未观察到表达。这种增加与黏附分子表达降低呈负相关。发现 B-CLL 中的 HGF 血清水平增加。体外实验表明，HGF 支持 B-CLL 细胞的存活，支持 HGF/c-met 途径在 B-CLL 中的可能功能。此外，还发现了 VLA-4 和 HGF/c-met 系统共有的关键信号分子的表达增加，包括 Bcl-XL、Akt、PI3K 和磷酸化 bad(136)，这是在 B-CLL 细胞受到 HGF 刺激后。
c-met 和 HGF 的表达增加可能绕过关键黏附分子表达的重要性，并支持 B-CLL 细胞的存活。c-met 作为表面酪氨酸激酶之一，可能成为未来 B-CLL 治疗的靶点，值得更多关注。
