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 population self-renewal, whereas 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.

JAK2 激酶的过度激活是人类Ph−骨髓增生性肿瘤 (MPN)的一个共同特征，最常见的是由于JAK2 V617F突变。Jak2基因座带有同源突变的小鼠表现出类似于真性红细胞增多症的表型。尽管 NFκB 通路基因缺乏突变，但包括 MPN 在内的骨髓肿瘤中仍存在 NFκB 通路过度激活。为了确定 NFκB 通路过度激活与 Jak2 V617F 结合的影响，我们利用了Ikk2 ( Ikk2 -CA) 小鼠。泛造血Ikk2 -CA 单独产生造血干细胞和 B 细胞的耗竭。当与Jak2 V617F突变结合时，Ikk2 -CA 挽救了Jak2 V617F的真性红细胞增多症表型。同样，Jak2 V617F改善了Ikk2 -CA产生的造血缺陷。造血干细胞和祖细胞的单细胞 RNA 测序揭示了 Jak2 和 Ikk2 拮抗调节的多个基因，包括其表达被Jak2 V617F和/或Ikk2 -CA改变但在双突变体中部分或完全纠正的亚群。我们假设 Jak2 促进造血干细胞群自我更新，而 Ikk2 促进骨髓谱系分化，并在造血的几个分支点偏向细胞命运。Jak2 和 Ikk2 均调节影响骨髓成熟和细胞死亡的多个基因。因此，Jak2 和 NFκB 双重过度激活的存在可能会导致骨髓肿瘤的新形态治疗脆弱性。