Fas/Apo-1(CD95) expression and apoptosis in patients with myelodysplastic syndromes
Fas/Apo-1(CD95) expression and apoptosis in patients with myelodysplastic syndromes
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DOI：
10.1038/sj.leu.2400654
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发表时间：
1997-06-01
期刊：
影响因子：
11.4
通讯作者：
FontenayRoupie, M
中科院分区：
文献类型：
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作者：
Bouscary, D;DeVos, J;FontenayRoupie, M
骨髓增生异常综合征(MDS)患者造血祖细胞的凋亡率增加。对27例MDS患者(RARS 4例，RA3例，RAEB 13例；RAEB-T 3例，CMML 4例)及3例继发于MDS的AML患者的Fas(CD95/Apo-1)抗原表达进行了研究。我们发现Fas抗原在正常骨髓CD34(+)、CD14(+)和血糖素(+)细胞上不表达，在CD33(+)细胞上仅有少量表达。骨髓有核细胞Fas表达上调(t检验，P=0.04)、CD34(+)(P=0.013)、CD33(+)(P=0.04)、糖蛋白(+)(P=0.032)。PAS的表达与FAB亚型、伯恩茅斯评分或外周血细胞减少无关。CD34(+)细胞Fas表达强度与骨髓原始细胞数呈负相关(Spearman，P=0.01)，提示随着骨髓增生异常的进展，白血病原始细胞Fas抗原表达缺失。用液体培养的增殖试验和在激动剂抗Fas单抗(CH11)存在下的克隆性祖细胞试验，我们发现在某些患者中Fas蛋白是有功能的。在被研究的7名患者中，有3名观察到了剂量依赖性的DNA合成抑制。部分患者的CFU-GM和BFU-E集落抑制提示Fas可诱导MDS患者骨髓和红系BM祖细胞发生凋亡，TUNEL法检测骨髓涂片显示5例正常对照骨髓细胞平均凋亡率为12.6%+/-2.5。骨髓细胞凋亡率增加(平均39%+/-5.70，t检验，P=0.012)。用灵敏的放射性标记DNA梯形技术研究的15名患者中，有4名(26%)有典型的DNA梯形图，表明细胞凋亡处于晚期。RA(2/2)和RAEB(8/11)患者骨髓大量自杀，RAEB-t(3/3)和继发性AMLS(3/3)患者细胞凋亡率正常或低。此外，高凋亡率与低伯恩茅斯评分相关(Spearman，P=0.01)。Fas表达与细胞凋亡率之间无统计学相关性。我们的结果证实了细胞程序性死亡在MDS中的重要性，Fas抗原在骨髓细胞上明显上调，但其在骨髓发育不良中的凋亡病理生理学中的作用尚不清楚，表明许多因素在体内和体外都对Fas介导的细胞凋亡途径产生了积极或消极的干扰。
Apoptosis of hematopoietic progenitor cells is increased in myelodysplastic syndromes (MDS). We have studied Fas (CD95/Apo-1) antigen expression in 27 MDS patients (RARS 4, RA 3, RAEB 13; RAEB-t 3, CMML 4) and three AML secondary to MDS. We found that the Fas antigen was not expressed on normal bone marrow (BM) CD34(+), CD14(+), or glycophorin(+) cells, and only slightly on CD33(+) cells. Patients with MDS had upregulation of Fas expression on total bone marrow nuclear cells (BMMC) (t-test, P = 0.04), CD34(+) (P = 0.013), CD33(+) (P = 0.04), and glycophorin(+) (P = 0.032) BM cells compared to controls. Pas expression did not correlate to the FAB subtype, the Bournemouth score, or to peripheral cytopenias. However, Fas expression intensity on CD34(+) cells negatively correlated to the BM blasts number (Spearman, P = 0.01) suggesting that leukemic blasts cells lose Fas antigen expression with progression of myelodysplasia. Using both proliferation assays in liquid cultures and clonogenic progenitor assays in the presence of an agonist anti-Fas MoAb (CH11), we showed that the Fas protein was functional in some patients. Dose-dependent inhibition of DNA synthesis was observed in three out of seven patients studied. CFU-GM and BFU-E colonies suppression in some patients suggested that Fas can induce apoptosis in myeloid and erythroid BM progenitors of MDS patients, The TUNEL technique on BM smears gave a mean of 12.6% +/- 2.5 of bone marrow apoptotic cells in five controls. Patients with MDS had increased bone marrow apoptosis (mean 39% +/- 5.7, t-test, P = 0.012). Four out of 15 (26%) patients studied with a sensitive radiolabeled DNA ladder technique had typical DNA ladders indicative of advanced stages of apoptosis. Massive BM suicide was observed in patients with RA (2/2) and RAEB (8/11), whereas apoptosis rates were normal or low in patients with RAEB-t (3/3) or secondary AMLs (3/3). Moreover, high rates of apoptosis correlated to low Bournemouth score (Spearman, P = 0.01). No statistical correlation could be found between Fas expression and apoptosis rates. Our results confirm the importance of programmed cell death in MDS, The Fas antigen is clearly upregulated on BM cells, but its role in the pathophysiology of apoptosis in myelodysplasia is still unclear, indicating that many factors positively or negatively interfere with the Fas-mediated pathway of apoptosis in vivo and in vitro.