Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

Abstract

Key Points• Emerging HSCs require Jak2 and Pi3k signaling for proliferation and survival.• Embryonic HSCs are unaffected by the JAK2V617F mutation.The regulation of hematopoietic stem cell (HSC) emergence during development provides important information about the basic mechanisms of blood stem cell generation, expansion, and migration. We set out to investigate the role that cytokine signaling pathways play in these early processes and show here that the 2 cytokines interleukin 3 and thrombopoietin have the ability to expand hematopoietic stem and progenitor numbers by regulating their survival and proliferation. For this, they differentially use the Janus kinase (Jak2) and phosphatidylinositol 3-kinase (Pi3k) signaling pathways, with Jak2 mainly relaying the proproliferation signaling, whereas Pi3k mediates the survival signal. Furthermore, using Jak2-deficient embryos, we demonstrate that Jak2 is crucially required for the function of the first HSCs, whereas progenitors are less dependent on Jak2. The JAK2V617F mutation, which renders JAK2 constitutively active and has been linked to myeloproliferative neoplasms, was recently shown to compromise adult HSC function, negatively affecting their repopulation and self-renewal ability, partly through the accumulation of JAK2V617F-induced DNA damage. We report here that nascent HSCs are resistant to the JAK2V617F mutation and show no decrease in repopulation or selfrenewal and no increase in DNA damage, even in the presence of 2 mutant copies. More importantly, this unique property of embryonic HSCs is stably maintained through ‡1 round of successive transplantations. In summary, our dissection of cytokine signaling in embryonic HSCs has uncovered unique properties of these cells that are of clinical importance.

Distinct effects of V617F and exon12-mutated JAK2 expressions on erythropoiesis in a human induced pluripotent stem cell (iPSC)-based model

“…A possible limitation of our model is that iPSC-derived hematopoietic stem cells (HSCs) might show different properties compared with the marrow-derived HSCs. Mascarenhas et al revealed that the mouse embryonic HSCs were relatively resistant to JAK2V617F mutation compared with adult HSCs 16 . Consistent with this finding, we found that JAK2V617F expression also showed minor effects on erythropoiesis from human iPSCs.…”

The MLL/SET family and haematopoiesis

“…How MLL/SET proteins function during the establishment of the haemogenic endothelium and/or early primitive haematopoietic progenitors remains underexplored ( Table 1 ). Given the multi-domain nature of MLL/SET and that foetal blood cells are distinct from their adult counterparts, it is entirely possible that new molecular mechanisms could be found [ 154 , 156 ]. As noted in Table 1 , there is much to learn about the developmental phenotypes of the MLL/SET family.…”

“…Whilst there will be conservation in the mechanisms derived from CB or ESC towards the molecular processing that is directed when the fusion occurs in vivo, modelling how MLL fusions impact foetal haematopoiesis with relevant timing is essential to uncovering the characteristics of the infant disease. Indeed, foetal HSPCs possess distinct molecular characteristics that are the result of foetal-specific intrinsic and extrinsic factors, and the cell of origin for the disease is known to be a critical determinant towards the resulting pathology [ 131 , 144 , [153] , [154] , [155] , [156] , [157] , [158] ]. Accordingly, identical knock-in models of adult MLL-AF9 and MLL-ENL leukaemia have shown that disease originates more efficiently from different HSPC populations when comparing both fusions, and that MLL-AF9 expression in LT-HSC causes a more aggressive leukaemia as compared to disease derived from GMP [ 157 , 159 ].…”

c-Kit-Positive Adipose Tissue-Derived Mesenchymal Stem Cells Promote the Growth and Angiogenesis of Breast Cancer

“…Moreover, the release of membrane-bound KitL, as an adhesion/survival-promoting molecule for stem cells, depends on IL-3 [ 34 ]. IL-3 acts as a nonspecific proinflammatory cytokine and drives cell proliferation by the JAK/STAT and PI3K/AKT pathways [ 35 – 37 ]. Our results demonstrated that c-Kit + ASCs stimulated IL-3 release both in vitro and in vivo.…”