JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response.
JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response.
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恶性细胞和非恶性细胞中的JAK-STAT途径激活有助于MPN的发病机理和治疗反应。
DOI：
10.1158/2159-8290.cd-14-0736
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发表时间：
2015-03
期刊：
影响因子：
28.2
通讯作者：
Levine RL
中科院分区：
文献类型：
--
作者：
Kleppe M;Kwak M;Koppikar P;Riester M;Keller M;Bastian L;Hricik T;Bhagwat N;McKenney AS;Papalexi E;Abdel-Wahab O;Rampal R;Marubayashi S;Chen JJ;Romanet V;Fridman JS;Bromberg J;Teruya-Feldstein J;Murakami M;Radimerski T;Michor F;Fan R;Levine RL
在骨髓增生性肿瘤（MPN）患者中发现JAK 2/MPL突变导致JAK激酶抑制剂（包括ruxolitinib）的临床开发。Ruxolitinib可减少骨髓纤维化（MF）患者的脾肿大和全身症状，并改善总生存期;然而，JAK抑制剂实现疗效的机制尚未阐明。MPN患者存在增加的循环促炎细胞因子水平，其通过JAK抑制剂治疗减轻。我们试图阐明JAK抑制剂减弱精氨酸介导的病理生理学的机制。单细胞分析表明，来自MF模型和患者样品的造血细胞异常分泌炎性细胞因子。泛造血Stat 3缺失降低了疾病的严重程度并减弱了细胞因子的分泌，其疗效与鲁索利替尼治疗相似。相比之下，仅限于MPN细胞的Stat 3缺失并没有降低疾病的严重程度或细胞因子的产生。与这些观察结果一致，我们发现恶性和非恶性细胞异常分泌细胞因子，JAK抑制减少了两个群体的细胞因子产生。
The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis (MF) and improves overall survival; however the mechanism by which JAK inhibitors achieve efficacy has not been delineated. MPN patients present with increased levels of circulating pro-inflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single cell profiling demonstrated that hematopoietic cells from MF models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. By contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and non-malignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations.