Complementary and countervailing actions of Jak2 and Ikk2 in hematopoiesis in mice

• Published in: Experimental hematology Vol. 128; pp. 48 - 66
• Main Authors: Fisher, Daniel A.C., Laranjeira, Angelo B.A., Kong, Tim, Snyder, Steven C., Shim, Kevin, Fulbright, Mary C., Oh, Stephen T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.12.2023
• Subjects: Animals; Hematopoiesis - genetics; Hematopoietic Stem Cells - metabolism; Humans; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Mice; Mutation; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Polycythemia Vera - genetics; Protein Serine-Threonine Kinases - genetics
• ISSN: 0301-472X; 1873-2399; 1873-2399
• DOI: 10.1016/j.exphem.2023.08.005

•Jak2 V617F and Ikk2-CA showed distinct and partly opposed effects on hematopoiesis.•Jak2 V617F and Ikk2-CA both antagonized frequency of transplantable hematopoietic stem cells (HSCs).•Ikk2 transcriptionally altered thrombopoietin signaling to favor Stat1 over Stat3 activation.•Double mutant gene expression suggested mutual antagonism in HSC but not GMP.•Ikk2 and Jak2/Ikk2 mutant HSC showed a propensity toward apoptosis ex vivo. 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. [Display omitted]