JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation
JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation
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DOI：
10.1038/s41375-018-0295-6
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发表时间：
2019-04-01
期刊：
影响因子：
11.4
通讯作者：
Koschmieder, Steffen
中科院分区：
文献类型：
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作者：
Czech, Julia;Cordua, Sabrina;Koschmieder, Steffen
聚乙二醇化干扰素-α（peg-IFNa）治疗诱导骨髓增生性肿瘤（MPN）患者的分子反应（MR），包括30-40%患者的部分MR（PMR）。在这里，我们比较了JAK 2 V617 F-与钙网蛋白（CALR）突变细胞中IFNa治疗的功效，并研究了差异反应的机制。对接受聚乙二醇-干扰素钠治疗的MPN患者的回顾性分析表明，携带JAK 2 V617 F突变的患者比携带突变CALR的患者更有可能实现PMR（p = 0.004），而血液学应答无显著差异。体外实验证实，与其CALR突变的对应物相比，JAK 2 V617 F阳性32 D细胞以及患者样品（外周血单核细胞和CD 34+造血干细胞）中IFN刺激的基因上调，并且需要更高的IFNa剂量才能在CALR中实现与JAK 2 V617 F突变32 D细胞相同的IFNa应答。此外，Janus激活激酶-1（JAK 1）和信号转导和转录激活因子1（STAT 1）在JAK 2 V617 F突变的细胞中显示组成性磷酸化，但在CALR突变的细胞中没有显示，表明启动了IFN α应答。此外，IFN诱导的生长停滞被选择性JAK 1抑制抵消，但被JAK 2抑制增强。总之，我们的数据表明，在临床上，CALR突变患者与JAK 2 V617 F阳性患者相比需要更高剂量的IFNa，并且我们提出了JAK 2 V617 F-JAK 1/STAT 1串扰模型，该模型导致JAK 2 V617 F阳性细胞对IFNa的引发，从而导致差异敏感性
Pegylated interferon-alpha (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F-vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/ STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity