Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia
Rattachement africain : de, gb. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
BACKGROUND: Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. METHODS: Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1β. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. RESULTS: Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. CONCLUSIONS: Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Neutrophil-specific expression of JAK2-V617F or CALRmut induces distinct inflammatory profiles in myeloproliferative neoplasia
- Date Crossref
- 09/06/2024
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
Otto-von-Guericke-Universität Magdeburg pays non établi dans la noticeUniversité ou école supérieure
-
Wellcome/MRC Cambridge Stem Cell Institute pays non établi dans la noticeStructure de recherche
-
University of Cambridge Cambridge Stem Cell Institute pays non établi dans la noticeUniversité ou école supérieure
-
Medizinische Hochschule Hannover pays non établi dans la noticeUniversité ou école supérieure
-
German Cancer Research Center Division of Translational Medical Oncology pays non établi dans la noticeStructure de recherche
-
Heidelberg University pays non établi dans la noticeUniversité ou école supérieure
-
National Center for Tumor Diseases pays non établi dans la noticeOrganisme public
-
Epigenomics (Germany) pays non établi dans la noticeEntreprise
-
Helmholtz Centre for Infection Research pays non établi dans la noticeStructure de recherche
-
Medical Faculty Department of Hematology pays non établi dans la noticeUniversité ou école supérieure
-
Otto-von-Guericke-University Inflammation and Infectiology (GC-I pays non établi dans la noticeUniversité ou école supérieure
-
Institute for Medical Microbiology and Hospital Epidemiology pays non établi dans la noticeStructure de recherche
Otto-von-Guericke-Universität Magdeburg, Wellcome/MRC Cambridge Stem Cell Institute et Cambridge Stem Cell Institute — University of Cambridge, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.