SDF-1/CXCR4在骨髓增生异常综合征患者中的生物学作用

Biological Behavior of SDF-1/CXCR4 in Patients with Myelodysplastic Syndrome

本研究主要探讨骨髓增生异常综合征(MDS)及白血病患者中基质细胞衍生因子-1(SDF-1)在细胞凋亡、迁移和黏附中的作用及相关的信号转导。选取37例初发MDS患者〔低危组(IPSS≤1.0)22例,高危组(IPSS≥1.5)15例〕、10例初发白血病患者及14例良性贫血患者(作为对照组),通过流式细胞术检测骨髓CD34+细胞表面CXCR4的表达水平及CD34+细胞的凋亡情况。选取4例低危MDS患者和5例高危MDS患者,通过微孔细胞迁移实验检测SDF-1对细胞的趋化作用。通过CCK-8法检测SDF-1对细胞之间黏附能力的影响。结果表明,低危MDS组骨髓内CD34+细胞的凋亡率明显高于高危MDS组(21.33%vs 7.27%,p<0.001),同样低危MDS组骨髓内CD34+细胞的凋亡率明显高于白血病组(21.33%vs 7.53%,p<0.001),未发现CD34+细胞的凋亡率与患者年龄性别有相关性。SDF-1能够促进高表达CXCR4患者的细胞黏附于基质细胞并能诱导该细胞的迁移,诱导细胞形态发生极化,上述作用可以被G蛋白抑制剂pertussis toxin、PI3K抑制剂wortmannin及CXCR4拮抗剂AMD3100明显抑制;而对低表达CXCR4的患者细胞则无上述抑制作用。结论:SDF-1/CXCR4通过PI3K信号通路提高细胞的迁移及黏附能力,发挥抗凋亡作用,上述作用可以被PI3K途径抑制剂和G蛋白抑制剂所阻断。

The purpose of this study was to evaluate the biological behavior of stromal cell-derived factor-l（SDF-1） in migration,adhesion and apoptosis as well as the related signaling transduction pathways in patients with myelodysplastic syndrome（MDS） and acute myeloid leukemia（AML）.37 patients with MDS,10 patients with de novo AML and 14 patients with non-clonal cytopenia diseases were chosen for this study. The expression level of CXCR4 on CD34^＋ cells and apoptosis of CD34^＋ cells in bone marrow were detected by flow cytometry;the chemotaxis of SDF-1 on bone marrow mononuclear cells in 4 patients with low risk MDS（IPSS score≤1.0） and 5 patients with high risk MDS（IPSS score≥1.5） was assayed by transwell migration test of cells.The effect of SDF-1 on cell adhesion capability was measured by using CCK-8 method.The results indicated that the apoptosis rate of CD34^＋ cells was significantly higher in MDS patients with low risk（IPPS score1.0） than that in MDS patients with high risk（IPSS score ≥1.5）（21.55% vs 7.52%,p〈0.001）;as well,the apoptosis rate of CD34^＋ cells was significantly higher in MDS patients with low risk than that in de novo AML patients（21.55% vs 7.33%,p〈0.001）,no relation of CD34^＋ cell apoptosis with age and sex of patients was found.SDF-1 could promote the cells of patients with CXCR4 high expression to adhere to the stroma cells,and induce migration of these cells,as well as,SDF-1 could trigger the polarization of the cells which highly expressed CXCR4.After addition of pertussis toxin,wortmannin and AMD3100,the ability of adhersion and migration of the cells with highly expressed CXCR4 decreased,but there was no abovementioned pheno-menon in patients who lowly expressed CXCR4.It is concluded that the SDF-1/CXCR4 axis enhances the ability of cell adhesion and nigration through PI3K signaling pathway,thereby plays antiapoptosis role,moreover the above-mentioned effects can be blocked by PI3K pathway inhibitor and G protein inhibitor.