Lewis N R, Pallis M, Russell N H
Department of Haematology, Nottingham City Hospital and University of Nottingham, Nottingham, United Kingdom.
Exp Hematol. 2000 May;28(5):535-42. doi: 10.1016/s0301-472x(00)00132-6.
To determine whether the Fas receptor-Fas ligand (FasR-FasL) system, which triggers apoptosis in sensitive cells, is an important mechanism of cytotoxicity in acute myeloblastic leukemia (AML).
We investigated FasR expression in primary AML cells and its upregulation by tumor necrosis factor (TNF), as well as the apoptosis induced by anti-Fas antibody and the potential interaction between the FasR-FasL system and the cytotoxic drug daunorubicin (DNR).
FasR was expressed on all 25 AML samples and three normal bone marrow harvests. The intensity of expression was variable (range 1. 6-2.1 in normal bone marrow CD34(+) cells and 1.5-5.1 in AML cells, median 2.4) and was related to the morphologic FAB classification, with the highest expression in FAB types M4 and M5 (range 1.6-5.1, median 3.2). No relationship was found between FasR expression and expression of the CD34 antigen. FasR was heterogeneously upregulated in all AML cells on treatment with TNF-alpha. The degree of FasR upregulation induced was found to be related to the FAB subtype, with the greatest response observed in immature FAB types M1, M2, and M6 (range 11.0-207.1%, median 48.7%). Apoptosis could be induced in all AML samples, but not in normal bone marrow CD34(+)ve cells, by the CH11 anti-FasR antibody, although the response was variable (range 4.1-37.6%, median 16.5%). The monocytic differentiated M4 and M5 AML cells exhibited the greatest sensitivity to Fas-mediated apoptosis (range 4.4-37.6, median 20.65%); however, no relationship was found between sensitivity to Fas-mediated apoptosis and FasR expression or CD34 positivity. Apoptosis in response to DNR was observed in all AML cases; however, sensitivity was heterogeneous and found to be unrelated to FasR expression or sensitivity to Fas-mediated apoptosis. The blocking anti-FasR antibody ZB4 blocked anti-FasR-mediated apoptosis but had no inhibitory effect on DNR-induced apoptosis in AML blasts. No cytotoxic synergistic effect was demonstrated when anti-FasR antibody was used in combination with DNR.
In AML, DNR induces apoptosis through an Fas-independent pathway. However, the induction of apoptosis through the Fas pathway might be a novel and effective approach for leukemia immunotherapy, particularly because Fas-mediated apoptosis was noted in CD34(+) and CD34(-) cases.
确定可触发敏感细胞凋亡的Fas受体 - Fas配体（FasR - FasL）系统是否是急性髓细胞白血病（AML）细胞毒性的重要机制。
我们研究了原发性AML细胞中FasR的表达及其被肿瘤坏死因子（TNF）上调的情况，以及抗Fas抗体诱导的凋亡，还有FasR - FasL系统与细胞毒性药物柔红霉素（DNR）之间的潜在相互作用。
在所有25份AML样本和3份正常骨髓采集样本中均检测到FasR表达。表达强度存在差异（正常骨髓CD34(+)细胞中范围为1.6 - 2.1，AML细胞中为1.5 - 5.1，中位数为2.4），且与形态学FAB分类相关，在FAB M4和M5型中表达最高（范围为1.6 - 5.1，中位数为3.2）。未发现FasR表达与CD34抗原表达之间存在关联。用TNF -α处理后，所有AML细胞中FasR均呈异质性上调。发现FasR上调程度与FAB亚型相关，在未成熟的FAB M1、M2和M6型中反应最大（范围为11.0 - 207.1%，中位数为48.7%）。CH11抗FasR抗体可诱导所有AML样本发生凋亡，但不能诱导正常骨髓CD34(+)细胞凋亡，不过反应存在差异（范围为4.1 - 37.6%，中位数为16.5%）。单核细胞分化的M4和M5 AML细胞对Fas介导的凋亡表现出最大敏感性（范围为4.4 - 37.6，中位数为20.65%）；然而，未发现对Fas介导凋亡的敏感性与FasR表达或CD34阳性之间存在关联。所有AML病例中均观察到对DNR的凋亡反应；然而，敏感性存在异质性，且与FasR表达或对Fas介导凋亡的敏感性无关。阻断性抗FasR抗体ZB4可阻断抗FasR介导的凋亡，但对AML原始细胞中DNR诱导的凋亡无抑制作用。抗FasR抗体与DNR联合使用时未显示出细胞毒性协同作用。
在AML中，DNR通过Fas非依赖途径诱导凋亡。然而，通过Fas途径诱导凋亡可能是白血病免疫治疗的一种新的有效方法，特别是因为在CD34(+)和CD34(-)病例中均观察到Fas介导的凋亡。
