Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera
Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera
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DOI：
10.1182/blood-2012-05-432989
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Lane, Steven W.
中科院分区：
文献类型：
--
作者：
Mullally, Ann;Bruedigam, Claudia;Lane, Steven W.
干扰素 - α（IFNα）是对骨髓增生性肿瘤（MPN）患者的有效治疗方法。除了诱导大多数MPN患者的血液学反应外，IFNα还减少了JAK2V617F等位基因负担，并可能使JAK2V617F突变克隆在某些患者中无法检测到。这些反应的基础机制尚不完全了解，以及由于IFNα对JAK2V617F突变干细胞的影响而发生的分子反应是否发生。使用JAK2V617F MPN的鼠模型，我们研究了IFN alpha对体内JAK2V617F MPN传播干细胞的影响。我们报告说，IFNα治疗会在模型中诱导血液学反应，并导致JAK2V617F MPN传播细胞的耗竭，从而损害疾病移植。我们证明，IFNα治疗诱导JAK2V617F突变体长期造血干细胞的细胞周期激活，并促进预定的红细胞分化分化程序。这些发现提供了对IFNα对JAK2V617F突变体和正常造血的差异作用的见解，并表明IFNα通过对MPN干细胞的影响实现MPN患者的分子缓解。此外，这些结果通过同时耗尽休眠的JAK2V617F MPN来支持MPN中的组合治疗方法，并用IFN alpha靶向使用JAK2抑制剂或细胞毒性化学疗法的增殖下游后代。
Interferon-alpha (IFN alpha) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFN alpha reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFN alpha on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFN alpha on Jak2V617F MPN-propagating stem cells in vivo. We report that IFN alpha treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFN alpha treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFN alpha on Jak2V617F mutant and normal hematopoiesis and suggest that IFN alpha achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN propagating stem cells with IFN alpha and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy.