The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression, and synapse formation
The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression, and synapse formation
复制标题
DOI：
10.4049/jimmunol.176.2.864
复制
发表时间：
2006-01-15
影响因子：
4.4
通讯作者：
Caignard, A
中科院分区：
文献类型：
--
作者：
Cebo, C;Da Rocha, S;Caignard, A
慢性粒细胞白血病是一种干细胞来源的克隆性多系骨髓增生性疾病，其特征是存在Bcr/Abl癌蛋白，一种组成型活性酪氨酸激酶。在以前的研究中，我们提供的证据表明，白血病细胞中Bcr/Abl过表达通过不同的机制增加了它们对NK介导的溶解的易感性。在本研究中，使用UT-7/9细胞，UT-7细胞的高水平Bcr/Abl转染子，我们表明，通过甲磺酸伊马替尼（IM），一种特异性Abl酪氨酸激酶抑制剂，治疗Ber/Abl靶，阻碍NK/靶免疫突触的形成。IM的主要作用包括诱导Bcr/Abl转染子表面GM 1神经节苷脂，从而防止与NK细胞相互作用后脂质筏中MHC相关Ag分子的重新分布。IM还影响靶标的细胞表面糖基化，如通过特异性凝集素的结合所评估的，所述特异性凝集素导致随后调节其与凝集素型NK受体（特别是NKG 2D）的结合。此外，我们证明，酪氨酸激酶活性抑制的结果在MHC相关的Ag-A/B和UL-16结合蛋白的表达减少Bcr/Abl转染子UT-7/9。我们发现，NKG 2D控制NK介导的UT-7/9细胞裂解，IM处理抑制了这一激活途径。总之，我们的研究结果表明，白血病细胞中Bcr/Abl的高表达通过酪氨酸激酶依赖性机制控制NKG 2D受体配体和膜GM 1的表达，IM对这些分子的调节干扰了NK细胞识别和转染子的细胞溶解。
Chronic myeloid leukemia is a clonal multilineage myeloproliferative disease of stem cell origin characterized by the presence of the Bcr/Abl oncoprotein, a constitutively active tyrosine kinase. In previous studies, we have provided evidence that Bcr/Abl overexpression in leukemic cells increased their susceptibility to NK-mediated lysis by different mechanisms. In the present study, using UT-7/9 cells, a high level Bcr/Abl transfectant of UT-7 cells, we show that the treatment of Ber/Abl target by imatinib mesylate (IM), a specific Abl tyrosine kinase inhibitor, hampers the formation of the NK/target immunological synapse. The main effect of IM involves an induction of surface GM1 ganglioside on Bcr/Abl transfectants that prevents the redistribution of MHC-related Ag molecules in lipid rafts upon interaction with NK cells. IM also affects cell surface glycosylation of targets, as assessed by binding of specific lectins resulting in the subsequent modulation of their binding to lectin type NK receptor, particularly NKG2D. In addition, we demonstrate that the tyrosine kinase activity repression results in a decrease of MHC-related Ags-A/B and UL-16-binding protein expression on Bcr/Abl transfectants UT-7/9. We show that NKG2D controls the NK-mediated lysis of UT-7/9 cells, and IM treatment inhibits this activating pathway. Taken together, our results show that the high expression of Bcr/Abl in leukemic cells controls the expression of NKG2D receptor ligands and membrane GM1 via a tyrosine kinase-dependent mechanism and that the modulation of these molecules by IM interferes with NK cell recognition and cytolysis of the transfectants.