文章：

甲磺酸伊马替尼抑制IL-7诱导的STAT5磷酸化，并促使慢性髓性白血病患者出现T细胞淋巴细胞减少

Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients

原文发布日期：2017-04-07

DOI: 10.1038/bcj.2017.29

类型: Original Article

开放获取: 是

英文摘要：

Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4+ counts in their blood, yet CD8+ counts are normal or even increased in some. Following the initiation of IM treatment, CD4+ counts were further diminished and CD8+ T lymphocytes were dramatically decreased. In vitro studies confirmed IM interference with TCR signaling through the inhibition of ERK phosphorylation and we showed a similar effect on IL-7 signaling and STAT5 phosphorylation (STAT5-p). Importantly however, using an in vivo mouse model, we demonstrated that IM impaired T cell survival through the inhibition of IL-7 and STAT5-p but not TCR signaling which remained unaffected during IM therapy. Thus, off-target inhibitory effects of IM on IL-7 and STAT5-p explain how T cell lymphopenia occurs in patients treated with IM.

摘要翻译： 

甲磺酸伊马替尼（IM）治疗已被证明可导致慢性髓系白血病（CML）患者T细胞计数降低，且有研究引用IM对T细胞受体（TCR）信号通路的干扰来解释这一现象。然而，IL-7与TCR信号对淋巴细胞存活均至关重要。本研究旨在探究IM是否通过干扰IL-7或TCR信号通路导致患者T细胞计数下降。确诊时，CML患者外周血中CD4+细胞计数通常较低，而CD8+细胞计数正常甚或部分患者升高。开始IM治疗后，CD4+细胞计数进一步减少，CD8+T淋巴细胞则急剧下降。体外研究证实IM通过抑制ERK磷酸化干扰TCR信号，并发现其对IL-7信号及STAT5磷酸化（STAT5-p）具有相似抑制作用。但重要的是，通过体内小鼠模型，我们证明IM通过抑制IL-7和STAT5-p（而非TCR信号）损害T细胞存活，TCR信号在IM治疗期间未受影响。因此，IM对IL-7和STAT5-p的脱靶抑制作用解释了接受IM治疗患者出现T淋巴细胞减少的机制。

原文链接：

Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients