The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition
The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition
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DOI：
10.1182/blood-2013-06-509976
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发表时间：
2013-11-21
期刊：
影响因子：
20.3
通讯作者：
Tyner, Jeffrey W.
中科院分区：
文献类型：
--
作者：
Fleischman, Angela G.;Maxson, Julia E.;Tyner, Jeffrey W.
我们最近在 60% 的慢性中性粒细胞白血病 (CNL) 和非典型（BCR-ABL 阴性）慢性粒细胞白血病 (aCML) 患者中发现了 CSF3R (GCSFR) 的靶向突变。在这里，我们证明最普遍的激活突变 CSF3R T618I 足以在小鼠骨髓移植模型中驱动致命的骨髓增殖性疾病。移植了表达 CSF3R T618I 的造血细胞的小鼠出现了骨髓增殖性疾病，其特征是粒细胞过度产生以及脾脏和肝脏的粒细胞浸润，这种疾病都是致命的。 JAK1/2 抑制剂鲁索替尼治疗降低了白细胞计数并减轻了脾脏重量。这表明 CSF3R 中的激活突变足以驱动类似于 aCML 和 CNL 的骨髓增殖性疾病，这些疾病对药理学 JAK 抑制敏感。该小鼠模型是进一步研究中性粒细胞性骨髓增生性肿瘤的绝佳工具，并暗示 JAK 抑制剂在该疾病中的临床应用。
We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration of the spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.