JAK2激酶的高度活化是Ph-型髓增生性肿瘤（MPNs）的一个统一特征，其中最常见的是JAK2 V617F突变引起的。在Jak2基因座中携带同源突变的小鼠表现出类似红细胞增多症的表型。尽管NFκB信号通路基因突变稀少，但其在髓系肿瘤中包括MPNs中具有高度活化。为了确定NFκB信号通路高活化与Jak2 V617F之间的影响，我们利用Ikk2（Ikk2-CA）小鼠。完整造血Ikk2-CA单独导致造血干细胞和B细胞的减少。当与Jak2 V617F突变结合时，Ikk2-CA挽救了Jak2 V617F的红细胞增多症表型。同样，Jak2 V617F改善了Ikk2-CA引起的造血缺陷。造血干细胞和祖细胞的单细胞RNA测序显示，Jak2和Ikk2拮抗调控了多个基因，包括一些亚群在Jak2 V617F和/或Ikk2-CA时表达发生改变，但在双突变体中部分或完全被纠正。我们假设Jak2促进造血干细胞（HSC）种群的自我更新，而Ikk2促进髓系细胞系分化，并在造血过程的几个分支点偏向不同的细胞命运。Jak2和Ikk2都调控多个影响粒系成熟和细胞死亡的基因。因此，同时存在Jak2和NFκB的高活化可能在髓系肿瘤中呈现新形态的治疗敏感性。版权所有©2023 Elsevier Inc.发表。

Hyperactivation of JAK2 kinase is a unifying feature of human Ph- myeloproliferative neoplasms (MPNs), most commonly due to the JAK2 V617F mutation. Mice harboring a homologous mutation in the Jak2 locus exhibit a phenotype resembling polycythemia vera. NFκB pathway hyperactivation is present in myeloid neoplasms, including MPNs, despite scarcity of mutations in NFκB pathway genes. To determine the impact of NFκB pathway hyperactivation in conjunction with Jak2 V617F, we utilized Ikk2 (Ikk2-CA) mice. Pan-hematopoietic Ikk2-CA alone produced depletion of hematopoietic stem cells and B cells. When combined with the Jak2 V617F mutation, Ikk2-CA rescued the polycythemia vera phenotype of Jak2 V617F. Likewise, Jak2 V617F ameliorated defects in hematopoiesis produced by Ikk2-CA. Single cell RNA sequencing of hematopoietic stem and progenitor cells revealed multiple genes antagonistically regulated by Jak2 and Ikk2, including subsets whose expression was altered by Jak2 V617F and/or Ikk2-CA, but partly or fully rectified in the double mutant. We hypothesize that Jak2 promotes hematopoietic stem cell (HSC) population self-renewal, while Ikk2 promotes myeloid lineage differentiation, and biases cell fates at several branch points in hematopoiesis. Jak2 and Ikk2 both regulate multiple genes affecting myeloid maturation and cell death. Therefore, the presence of dual Jak2 and NFκB hyperactivation may present neomorphic therapeutic vulnerabilities in myeloid neoplasms.Copyright © 2023. Published by Elsevier Inc.