Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.
Exp Hematol. 2010 Oct;38(10):885-95. doi: 10.1016/j.exphem.2010.06.014. Epub 2010 Jul 27.
Cytotoxic ligands are involved in tumor immunity and graft-vs.-leukemia effect after allogeneic stem cell transplantation for leukemia. To clarify the susceptibility of T-cell acute lymphoblastic leukemia (T-ALL) to tumor immunity, sensitivity to recombinant human soluble Fas ligand (rhsFasL) and tumor necrosis factor-related apoptosis-inducing ligand (rhsTRAIL) was determined.
Sensitivity to rhsFasL and rhsTRAIL and cell surface expression of their receptors were tested in T-ALL cell lines (n = 7) and patients' samples (n = 17) and compared with those in B-precursor ALL cell lines (n = 30). Expression of components of the death-inducing signaling complex and the TRAIL receptor genes (DR4/DR5), and the methylation status and promoter activity of the DR4/DR5 gene were tested in T-ALL cell lines.
T-ALL cell lines showed higher level of Fas expression and higher sensitivity to rhsFasL than did B-precursor ALL cell lines. Despite comparable expression of components of death-inducing signaling complex, cell lines and patients' samples of T-ALL showed TRAIL-resistance associated with low cell surface expression of DR4/DR5. Gene expression of DR4/DR5 in T-ALL cell lines was significantly lower than that in B-precursor ALL cell lines, and the methylation status of the gene promoter in T-ALL cell lines was associated with the gene expression level at least for DR4. The demethylating agent, 5-aza 2'deoxycytidine, upregulated the gene expression of DR4/DR5, but was insufficient for their surface expression due to low basal promoter activity.
In contrast to higher sensitivity to FasL, T-ALL showed resistance to TRAIL, which might be responsible for resistance to TRAIL-mediated cellular immunity.
细胞毒性配体参与异体造血干细胞移植治疗白血病后的肿瘤免疫和移植物抗白血病效应。为阐明 T 细胞急性淋巴细胞白血病（T-ALL）对肿瘤免疫的敏感性，检测了 T-ALL 细胞系（n=7）和患者样本（n=17）对重组人可溶性 Fas 配体（rhsFasL）和肿瘤坏死因子相关凋亡诱导配体（rhsTRAIL）的敏感性，并与前 B 细胞 ALL 细胞系（n=30）进行了比较。检测了 T-ALL 细胞系中诱导死亡信号复合物和 TRAIL 受体基因（DR4/DR5）的表达以及 DR4/DR5 基因的甲基化状态和启动子活性。
T-ALL 细胞系 Fas 表达水平较高，对 rhsFasL 的敏感性高于前 B 细胞 ALL 细胞系。尽管诱导死亡信号复合物的成分表达相似，但 T-ALL 细胞系和患者样本表现出与 DR4/DR5 细胞表面表达降低相关的 TRAIL 耐药性。T-ALL 细胞系中 DR4/DR5 的基因表达明显低于前 B 细胞 ALL 细胞系，DR4/DR5 基因启动子的甲基化状态与基因表达水平至少与 DR4 相关。去甲基化剂 5-氮杂 2'-脱氧胞苷上调了 DR4/DR5 的基因表达，但由于基础启动子活性低，不足以使其表面表达。
与 FasL 敏感性较高相反，T-ALL 对 TRAIL 表现出耐药性，这可能是其对 TRAIL 介导的细胞免疫产生耐药性的原因。
