Prevalence and clinical significance of resistance to perforin- and FAS-mediated cell death in leukemia
Prevalence and clinical significance of resistance to perforin- and FAS-mediated cell death in leukemia
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DOI：
10.1038/sj.leu.2403414
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发表时间：
2004-08-01
期刊：
影响因子：
11.4
通讯作者：
Petersen, EJ
中科院分区：
文献类型：
--
作者：
Otten, HG;van Ginkel, WGJ;Petersen, EJ
杀伤淋巴细胞在异基因造血干细胞移植（HSCT）后的移植物抗白血病中起着重要的治疗作用。穿孔蛋白/颗粒酶和FAS/CD 95途径在杀伤细胞消除肿瘤细胞中至关重要。在这项研究中，我们检查了血液恶性肿瘤是否对穿孔素和抗FAS抗体耐药。研究了29例急性或慢性髓性白血病（AML或CML）、急性或慢性淋巴细胞白血病或非霍奇金淋巴瘤患者的白血病细胞。当使用穿孔素与抗FAS抗体时，分别发现平均49%与5%的特异性细胞杀伤。有趣的是，对穿孔素和抗FAS抗体的耐药性仅在骨髓白血病患者的白血病细胞中发现。对HSCT后白血病复发并给予供体淋巴细胞输注（DLI）诱导缓解的CML患者的白血病细胞进行分析，结果表明DLI治疗的有效性与白血病细胞对穿孔素的敏感性无关。总之，抗FAS抗体耐药是白血病/淋巴瘤中的常见现象，而穿孔素耐药仅发生在髓系白血病中。然而，作为一个单一的参数，穿孔素抵抗似乎并不适合预测DLI的结果。
Killer lymphocytes play a central therapeutic role in graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT). The Perforin/Granzyme and FAS/CD95 pathways are of crucial importance in tumor cell elimination by killer cells. In this study, we have examined whether hematological malignancies are resistant to perforin and anti-FAS antibodies. Leukemic cells were studied from 29 patients suffering either from acute or chronic myeloid leukemia (AML or CML), acute or chronic lymphoid leukemia, or non-Hodgkin's lymphoma. An average of 49 vs 5% of specific cell killing was found when using perforin vs anti-FAS antibodies, respectively. Interestingly, resistance towards both perforin and anti-FAS antibodies was found exclusively in leukemic cells from patients with myeloid leukemia. Analysis of leukemic cells from patients with CML, suffering from leukemia relapse after HSCT and given donor lymphocyte infusion (DLI) to induce remission, indicated that the effectiveness of treatment with DLI was not associated with sensitivity of leukemic cells to perforin. In conclusion, resistance towards anti-FAS antibodies is a common phenomenon in leukemia/lymphoma, whereas perforin resistance occurs only in myeloid leukemia. However, as a single parameter, perforin resistance does not appear to be suitable to predict the outcome of DLI.