Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPNs), most commonly JAK2V617F. While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined, Dre-rox/Cre-lox dual recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when co-occurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.

中文翻译：

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Jak2V617F 可逆激活显示其在骨髓增生性肿瘤中的必要条件

大多数骨髓增生性肿瘤 (MPN) 患者中都存在激活 JAK/STAT 信号传导的功能获得突变，最常见的是 JAK2V617F。虽然临床批准的 JAK 抑制剂可改善 MPN 的症状和结果，但缓解很少见，并且突变等位基因负担不会因长期治疗而发生实质性改变。我们假设这是由于当前 JAK 抑制剂在有效且特异性地消除突变型 JAK2 信号传导方面存在局限性。因此，我们开发了一种条件诱导小鼠模型，允许使用组合的 Dre-rox/Cre-lox 双重组酶系统从其内源基因座顺序激活 Jak2V617F，然后失活。Jak2V617F 缺失消除了 MPN 特征，诱导突变体特异性造血干细胞/祖细胞的耗竭，并将总体生存期延长至药物 JAK 抑制未观察到的程度，包括与体细胞 Tet2 缺失同时发生时。我们的数据表明 JAK2V617F 代表了 MPN 中的最佳治疗靶点，并证明了双重组酶系统在评估体内突变体特异性致癌依赖性方面的治疗相关性。