Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function.
Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function.
复制标题
CSF3R 不成对的细胞外半胱氨酸突变介导功能的获得或丧失。
DOI：
10.1158/0008-5472.can-17-1052
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发表时间：
2017
期刊：
影响因子：
11.2
通讯作者：
Tyner,JeffreyW
中科院分区：
文献类型：
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作者：
Zhang,Haijiao;Means,Sophie;Schultz,AnnaReister;Watanabe-Smith,Kevin;Medeiros,BrunoC;Bottomly,Daniel;Wilmot,Beth;McWeeney,ShannonK;Kükenshöner,Tim;Hantschel,Oliver;Tyner,JeffreyW
排除慢性嗜中性粒细胞白血病中常见的近膜突变（例如，T618 I），G-CSF受体（CSF 3R）胞外结构域的功能缺陷突变仅在严重的先天性和特发性中性粒细胞减少症患者中报道。在这里，我们描述的第一个激活突变的纤连蛋白样的CSF 3R（W341 C）的细胞外区域的III型结构域的白血病患者。这种突变通过半胱氨酸介导的分子间二硫键转化细胞，导致受体二聚化。有趣的是，在与细胞外突变相同的等位基因上发现的CSF 3R胞质截短突变（W791 X）和复合突变的扩展与患者的白细胞增多和疾病进展相关。值得注意的是，原代患者样品和W341 C和W341 C/W791 X转化的细胞显示出对JAK抑制剂的敏感性。我们进一步表明，CSF 3R胞外结构域中原始半胱氨酸对的破坏导致功能改变的获得或丧失，其中部分可归因于半胱氨酸介导的二聚体形成。因此，这代表了介导功能获得和丧失表型的未配对半胱氨酸的第一个表征。总之，我们的结果显示了CSF 3R中保守的胞外半胱氨酸对的结构和功能重要性，并表明在白血病患者中更广泛地筛选CSF 3R胞外结构域的必要性。©2017 AACR.
Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of-function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.Cancer Res; 77(16); 4258–67. ©2017 AACR.