TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells
TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells
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DOI：
10.1182/blood-2002-06-1770
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发表时间：
2003-05-01
期刊：
影响因子：
20.3
通讯作者：
Nakazawa, S
中科院分区：
文献类型：
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作者：
Uno, K;Inukai, T;Nakazawa, S
肿瘤坏死因子相关凋亡诱导配体（TRAIL）和Fas配体（FasL）参与抗肿瘤免疫和治疗。在本研究中，我们研究了费城染色体（Ph 1）阳性白血病细胞系对TRAIL或FasL诱导的细胞死亡的敏感性，以探讨这些分子对Ph 1阳性白血病免疫治疗的可能贡献。TRAIL，而不是FasL，有效地诱导大多数的5个慢性粒细胞白血病衍生的和7个急性白血病衍生的Phi阳性细胞系的细胞凋亡。对TRAIL的敏感性与死亡的细胞表面表达相关。诱导受体DR 4和/或DR 5。TRAIL诱导的细胞死亡是半胱天冬酶依赖性的，并通过核因子kappaB抑制剂增强。此外，来自Ph 1阳性急性淋巴细胞白血病患者的原代白血病细胞也对TRAIL敏感，但对FasL不敏感，这取决于DR 4/DR 5。表情Fas相关死亡结构域蛋白（FADD）和caspase-8，死亡诱导信号复合物（DISC）的组成部分，以及FLIP（FLICE [Fas相关蛋白与死亡结构域样白细胞介素-1转换酶]/caspase-8抑制蛋白），caspase-8的负调控因子，在Ph 1阳性白血病细胞系中普遍表达，而不管它们对TRAIL和FasL的敏感性如何。值得注意的是，TRAIL可以诱导BCR-ABL特异性酪氨酸激酶抑制剂甲磺酸伊马替尼（STI 571; Novartis Pharma，巴塞尔，瑞士）难治的Ph 1阳性白血病细胞系中的细胞死亡。这些结果表明，重组TRAIL作为一种新的治疗药物的潜在效用和可能的贡献。内源性表达的TRAIL的免疫治疗对Ph 1阳性白血病。(C)2003年，美国血液学会。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) have been implicated in antitumor immunity and therapy. In the present study, we investigated the sensitivity of Philadelphia chromosome (Ph1)-positive leukemia cell lines to TRAIL- or FasL-Induced cell death to explore the possible contribution of these molecules to immunotherapy against Ph1-positive leukemias. TRAIL, but not FasL, effectively induced apoptotic cell death in most of 5 chronic myelogenous leukemia-derived and 7 acute leukemia-derived Phi-positive cell lines. The sensitivity to TRAIL was correlated with cell-surface expression of death.-inducing receptors DR4 and/or DR5. The TRAIL-induced cell death was caspase-dependent and enhanced by nuclear factor kappaB inhibitors. Moreover, primary leukemia cells from Ph1-positive acute lymphoblastic leukemia patients were also sensitive to TRAIL, but not to FasL, depending on DR4/DR5. expression. Fas-associated death domain protein (FADD) and caspase-8, components of death-inducing signaling complex (DISC), as well as FLIP (FLICE [Fas-associating protein with death domain-like interleukin-1-converting enzyme]/caspase-8 inhibitory protein), a negative regulator of caspase-8, were expressed ubiquitously in Ph1-positive leukemia cell lines irrespective of their differential sensitivities to TRAIL and FasL. Notably, TRAIL could induce cell death in the Ph1-positive leukemia cell lines that were refractory to a BCR-ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571; Novartis Pharma, Basel, Switzerland). These re suits suggested the potential utility of recombinant TRAIL as a novel therapeutic agent and the possible contribution. of endogenously expressed TRAIL to immunotherapy against Ph1-positive leukemias. (C) 2003 by The American Society of Hematology.