Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.
Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.
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Jak2V617F 可逆激活显示了其在骨髓增殖性肿瘤中的基本要求。
DOI：
10.1158/2159-8290.cd-22-0952
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发表时间：
2024
期刊：
影响因子：
28.2
通讯作者：
Farina,
中科院分区：
文献类型：
--
作者：
Dunbar,AndrewJ;Bowman,RobertL;Park,YoungC;O'Connor,Kavi;Izzo,Franco;Myers,RobertM;Karzai,Abdul;Zaroogian,Zach;Kim,WonJun;Fernandez-Maestre,Ines;Waarts,MichaelR;Nazir,Abbas;Xiao,Wenbin;Codilupi,Tamara;Brodsky,Max;Farina,
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。尽管临床批准的 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 MPN 特征，诱导突变体特异性造血干/祖细胞的耗竭，并将总体生存期延长至药理学 JAK 未观察到的程度抑制，包括与体细胞Tet2丢失同时发生时。我们的数据表明 JAK2V617F 代表 MPN 中的最佳治疗靶点，并证明了双重组酶系统在体内评估突变体特异性致癌依赖性的治疗相关性。 意义 目前用于治疗骨髓增生性肿瘤的 JAK 抑制剂无法有效根除突变细胞。我们开发了一种内源性表达的 Jak2V617F 双重组酶敲入/敲除模型，以研究 Jak2V617F 体内致癌性逆转。Jak2V617F 缺失消除了 MPN 特征并耗尽了维持疾病的 MPN 干细胞，表明改进的 Jak2V617F 靶向提供了更大治疗效果的潜力。参见 Celik 和 Challen 的相关评论，第 17 页。 701.本文收录于本期精选文章，第 701 页。 695
Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonlyJAK2V617F. Although 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, ofJak2V617Ffrom its endogenous locus using a combined Dre-rox/Cre-loxdual-recombinase system.Jak2V617Fdeletion 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 cooccurring with somaticTet2loss. Our data suggest JAK2V617Frepresents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependenciesin vivo.SignificanceCurrent JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressedJak2V617Fdual-recombinase knock-in/knock-out model to investigateJak2V617Foncogenic reversionin vivo.Jak2V617Fdeletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617Ftargeting offers the potential for greater therapeutic efficacy.See related commentary by Celik and Challen, p. 701.This article is featured in Selected Articles from This Issue, p. 695