文章：

MLL–AFF1-阳性急性淋巴细胞白血病对肿瘤坏死因子- α的抗性是由S100A6上调介导的

Resistance of MLL–AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation

原文发布日期：2011-11-04

DOI: 10.1038/bcj.2011.37

类型: Original Article

开放获取: 是

英文摘要：

Mixed-lineage leukemia (MLL)–AFF1 (MLL–AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL–AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL–AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL–AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53–caspase 8–caspase 3 pathway were observed only in MLL–AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53–caspase 8–caspase 3 pathway of MLL–AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL–AFF1 transgenic mice. These results suggest that MLL–AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53–caspase 8–caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL–AFF1-positive ALL in combination with allo-HSCT.

摘要翻译： 

混合谱系白血病（MLL）-AFF1（MLL-AF4）阳性急性淋巴细胞白血病（ALL）预后不良，即使在异基因造血干细胞移植（allo-HSCT）后亦然。其对移植物抗白血病（GVL）效应的抵抗可能是导致allo-HSCT对MLL-AFF1阳性ALL疗效不佳的原因。据报道，肿瘤坏死因子-α（TNF-α）介导的细胞毒性效应机制有助于GVL效应。我们发现MLL-AFF1阳性ALL细胞系对TNF-α具有抵抗性。为探究MLL-AFF1阳性白血病对TNF-α的抵抗机制，我们聚焦于S100A6作为潜在影响因素。仅在MLL-AFF1阳性ALL细胞系中，在TNF-α存在下观察到S100A6表达上调和p53–caspase 8–caspase 3通路抑制。通过使用针对S100A6的小干扰RNA进行分析，进一步证实了S100A6通过抑制p53–caspase 8–caspase 3通路对MLL-AFF1阳性ALL细胞系TNF-α抵抗性的影响。该通路在既往建立的MLL–AFF1转基因小鼠中也得到验证。这些结果表明，MLL–AFF1阳性ALL通过上调S100A6表达并干扰p53–caspase 8–caspase 3通路，从而逃逸TNF-α介导的细胞凋亡。这些发现提示S100A6可能成为联合allo-HSCT治疗MLL–AFF1阳性ALL的潜在治疗靶点。

原文链接：

Resistance of MLL–AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation