The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I.
The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I.
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DOI：
10.1158/1078-0432.ccr-14-3100
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发表时间：
2016-02-01
期刊：
影响因子：
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通讯作者：
Tyner JW
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文献类型：
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作者：
Maxson JE;Luty SB;MacManiman JD;Paik JC;Gotlib J;Greenberg P;Bahamadi S;Savage SL;Abel ML;Eide CA;Loriaux MM;Stevens EA;Tyner JW
CSF 3R突变已在大多数慢性嗜中性粒细胞白血病（CNL）和较小比例的非典型慢性髓细胞白血病（aCML）病例中发现。虽然CSF 3R点突变（例如T618 I）正在成为CNL/aCML的关键参与者，但罕见的CSF 3R突变的意义尚不清楚。在这项研究中，我们评估了CSF 3R T640 N突变作为CNL/aCML标志物和潜在治疗靶点的重要性。对白血病样品进行桑格测序以鉴定CNL和aCML中的CSF 3R突变。通过细胞因子非依赖性生长试验和小鼠骨髓移植评估CSF 3R T640 N突变相对于T618 I突变的致癌性。通过蛋白质印迹评估突变体的受体二聚化和0-糖基化，并且通过集落测定评估JAK抑制剂敏感性。在这里，我们确定了CSF 3R T640 N突变的CNL/aCML患者，其中一人最初被诊断为MDS，并获得T640 N突变后，疾病演变为aCML。T640 N突变在细胞转化试验和体内小鼠骨髓移植模型中是致癌的。它表现出许多与T618 I相似的表型特征，包括配体独立性和改变的O-糖基化模式-尽管T640的跨膜位置阻止了GalNAc转移酶的进入。通过T640 N突变转化的细胞对JAK激酶抑制的敏感性与通过CSF 3R T618 I转化的细胞相似。由于其与CSF 3R T618 I的相似性，T640 N突变可能在CNL/aCML中具有诊断和治疗相关性。
CSF3R mutations have been identified in the majority of chronic neutrophilic leukemia (CNL) and a smaller percentage of atypical chronic myeloid leukemia (aCML) cases. Although CSF3R point mutations (e.g. T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target. Sanger sequencing of leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by western blot, and JAK inhibitor sensitivity was assessed by colony assay. Here we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation – despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I. Due to its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML.