Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutationReportar como inadecuado


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


Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Publication Date: 2016-02-10

Journal Title: Blood

Publisher: American Society of Hematology

Type: Article

Metadata: Show full item record

Citation: Mascarenhas, M. I., Bacon, W. A., Kapeni, C., Fitch, S. R., Kimber, G., Cheng, S. W. P., Li, J., et al. (2016). Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation. Blood

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Abstract: 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 two 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 employ the Jak2 and Pi3k signaling pathways, with Jak2 mainly relaying the pro-proliferation signaling, while Pi3k mediates the survival signal. Furthermore, using Jak2-deficient embryos, we demonstrate that Jak2 is crucially required for the function of the first HSCs, while progenitors are less dependent on Jak2. The JAK2V617F mutation, which renders JAK2 constitutively active and which 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 self-renewal and no increase in DNA damage, even in the presence of two mutant copies. More importantly, this unique property of embryonic HSCs is stably maintained through at least one 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.

Sponsorship: Core facilities are supported by Strategic Award WT100140 and equipment grant 093026. This work was funded by a Medical Research Council PhD Studentship (M.I.M.), by a Kay Kendall Leukaemia Fund Intermediate Fellowship (KKL276, K.O.), a Leukaemia & Lymphoma Research Bennett Senior Fellowship (10015, K.O.) and a British Society for Haematology Early Stage Investigator Fellowship (K.O.). The authors have no conflicting financial interests.

Identifiers:

This record's URL: http://dx.doi.org/10.1182/blood-2015-08-664631https://www.repository.cam.ac.uk/handle/1810/254767





Autor: Mascarenhas, Maria I.Bacon, Wendi A.Kapeni, ChrysaFitch, Simon R.Kimber, GillianCheng, S. W. PriscillaLi, JuanGreen, Anthony R.Ott

Fuente: https://www.repository.cam.ac.uk/handle/1810/254767



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