TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms
TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms
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DOI：
10.1182/blood-2011-04-348144
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发表时间：
2011-12-08
期刊：
影响因子：
20.3
通讯作者：
Deininger, Michael W.
中科院分区：
文献类型：
--
作者：
Fleischman, Angela G.;Aichberger, Karl J.;Deininger, Michael W.
促炎细胞因子如TNF α在骨髓增生性肿瘤（MPN）患者中升高，但其对疾病发病机制的作用尚不清楚。在这里，我们揭示了TNF α在促进MPN中JAK 2（V617 F）表达细胞的克隆优势中的核心作用。我们发现JAK 2（V617 F）激酶调节细胞系和原代MPN细胞中的TNF α表达，并且TNF α表达与JAK 2（V617 F）等位基因负荷相关。在克隆形成测定中，正常对照显示在TNF α存在下集落形成减少，而JAK 2（V617 F）阳性祖细胞的集落形成是耐受的或通过暴露于TNF α而刺激。异位JAK 2（V617 F）表达赋予正常鼠祖细胞TNF α抗性并克服范可尼贫血互补C族缺陷祖细胞的固有TNF α超敏性。最后，在JAK 2（V617 F）阳性MPN的鼠模型中，TNF α的缺乏限制了克隆扩增并减轻了疾病。总之，我们的数据与JAK 2（V617 F）通过赋予肿瘤前TNF α敏感细胞TNF α抗性，同时产生富含TNF α的环境来促进克隆选择的模型一致。突变，赋予抵抗环境干细胞应激是一个公认的机制，克隆选择和白血病的骨髓衰竭综合征，我们的数据表明，这种机制也是至关重要的MPN的克隆选择。（血。2011;118（24）：6392-6398）
Proinflammatory cytokines such as TNF alpha are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNF alpha in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNF alpha expression in cell lines and primary MPN cells and TNF alpha expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNF alpha while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNF alpha. Ectopic JAK2(V617F) expression confers TNF alpha resistance to normal murine progenitor cells and overcomes inherent TNF alpha hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNF alpha limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNF alpha resistance to a preneoplastic TNF alpha sensitive cell, while simultaneously generating a TNF alpha-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN. (Blood. 2011;118(24):6392-6398)