Thiant S, Moutuou M M, Laflamme P, Sidi Boumedine R, Leboeuf D M, Busque L, Roy J, Guimond M
Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.
Départment de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
Blood Cancer J. 2017 Apr 7;7(4):e551. doi: 10.1038/bcj.2017.29.
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.
甲磺酸伊马替尼（IM）治疗已被证明会导致慢性粒细胞白血病（CML）患者的T细胞计数降低，有人提出IM对T细胞受体（TCR）信号传导的干扰来解释这一观察结果。然而，白细胞介素-7（IL-7）和TCR信号传导对淋巴细胞存活均至关重要。本研究旨在确定IM是否干扰IL-7或TCR信号传导，以解释患者T细胞计数降低的原因。在诊断时，CML患者血液中的CD4计数通常较低，但在某些患者中CD8计数正常甚至升高。开始IM治疗后，CD4计数进一步减少，CD8 T淋巴细胞显著减少。体外研究证实IM通过抑制细胞外信号调节激酶（ERK）磷酸化干扰TCR信号传导，并且我们对IL-7信号传导和信号转导及转录激活因子5磷酸化（STAT5-p）也显示出类似作用。然而，重要的是，使用体内小鼠模型，我们证明IM通过抑制IL-7和STAT5-p损害T细胞存活，但不影响TCR信号传导，在IM治疗期间TCR信号传导保持未受影响。因此，IM对IL-7和STAT5-p的脱靶抑制作用解释了接受IM治疗的患者中T细胞淋巴细胞减少的发生机制。
