Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA378381 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Transplant recipients of IDH2-R140Q JAK2-V617F expressing bone marrow were treated with AG221 and ruxolitinib monotherapy, combined therapy, or vehicle. LSKs were sorted from terminal samples and sequenced with three WT controls.
2018-02-22 | GSE95771 | GEO
Project description:Pegylated interferon alpha (pegIFNα) can induce molecular remissions in JAK2-V617F-positive myeloproliferative neoplasms (MPN) patients by targeting long-term hematopoietic stem cells (LT-HSCs). Additional somatic mutations in genes regulating LT-HSC self-renewal, such as DNMT3A, have been reported to have poorer responses to pegIFNα. We investigated if DNMT3A loss leads to alterations in JAK2-V617F LT-HSCs functions conferring resistance to pegIFNα treatment in a mouse model of MPN and in hematopoietic progenitors from MPN patients. Long-term treatment with pegIFNα normalized blood parameters, reduced splenomegaly and JAK2-V617F-chimerism in single-mutant JAK2-V617F (VF) mice. However, pegIFNα in VF;Dnmt3aΔ/Δ (VF;DmΔ/Δ) mice worsened splenomegaly and failed to reduce JAK2-V617F-chimerism. Furthermore, LT-HSCs from VF;DmΔ/Δ mice compared to VF were less prone to accumulate DNA damage and exit dormancy upon pegIFNα treatment. RNA-sequencing showed that IFNα induced stronger upregulation of inflammatory pathways in LT-HSCs from VF;DmΔ/Δ compared to VF mice, indicating that the resistance of VF;DmΔ/Δ LT-HSC was not due to failure in IFNα signaling. Transplantations of bone marrow from pegIFNα treated VF;DmΔ/Δ mice gave rise to more aggressive disease in secondary and tertiary recipients. Liquid cultures of hematopoietic progenitors from MPN patients with JAK2-V617F and DNMT3A mutation showed increased percentages of JAK2-V617F-positive colonies upon IFNα exposure, whereas in patients with JAK2-V617F alone the percentages of JAK2-V617F-positive colonies decreased or remained unchanged. PegIFNα combined with 5-azacytidine only partially overcame resistance in VF;DmΔ/Δ mice. However, this combination strongly decreased the JAK2-mutant allele burden in mice carrying VF mutation only, showing potential to inflict substantial damage preferentially to the JAK2-mutant clone.
2024-03-29 | GSE255253 | GEO
Project description:JAK2-V617F is the most frequent somatic mutation causing myeloproliferative neoplasm (MPN). JAK2-V617F can be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the prevalence of MPN. The factors controlling the conversion of JAK2-V617F CHIP to MPN are largely unknown. We hypothesized that IL-1β mediated inflammation can favor this progression. We established an experimental system using bone marrow (BM) transplantations from JAK2-V617F and GFP transgenic (VF;GFP) mice, that were further crossed with IL-1β-/- or IL-1R1-/- mice. To study the role of IL-1β and its receptor on monoclonal evolution of MPN, we performed competitive BM transplantations at high dilutions with only 1-3 hematopoietic stem cells (HSCs) per recipient. Loss of IL-1β in JAK2-mutant HSCs reduced engraftment, restricted clonal expansion, lowered the total numbers of functional HSCs, and decreased the rate of conversion to MPN. Loss of IL-1R1 in the recipients also lowered the conversion to MPN, but did not reduce the frequency of engraftment of JAK2-mutant HSCs. WT recipients transplanted with VF;GFP BM that developed MPN had elevated IL-1β levels and reduced frequencies of mesenchymal stromal cells (MSCs). Interestingly, frequencies of MSCs were also reduced in recipients that did not develop MPN, had only marginally elevated IL-1β levels and displayed low GFP-chimerism resembling CHIP. Anti-IL-1β antibody preserved high frequencies of MSCs in VF;GFP recipients and reduced the rate of engraftment and the conversion to MPN. Our results identify IL-1β as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPN.
2024-01-29 | GSE250507 | GEO
Project description:The JAK2 mutation V617F is detectable in a majority of patients with Ph-negative myeloproliferative neoplasms (MPN). Enforced expression of JAK2 V617F in mice induces myeloproliferation and bone marrow (BM) fibrosis suggesting a causal role for the JAK2 mutant in the pathogenesis of MPN. However, little is known about mechanisms and effector molecules contributing to JAK2 V617F-induced myeloproliferation and fibrosis. Here we show that JAK2 V617F promotes expression of oncostatin M (OSM) in neoplastic myeloid cells. Correspondingly, OSM was found to be overexpressed in the BM and elevated in the serum of patients with JAK2 V617F+ MPN. In addition, OSM secreted by JAK2 V617F+ cells stimulated growth of fibroblasts and microvascular endothelial cells and induced the production of angiogenic and profibrogenic cytokines (HGF, VEGF, and SDF-1) in BM fibroblasts. All effects of MPN cell-derived OSM were blocked by a neutralizing anti-OSM antibody, whereas the production of OSM in MPN cells was effectively suppressed by a pharmacologic JAK2 inhibitor or RNAi-mediated knockdown of JAK2. In summary, JAK2 V617F-mediated upregulation of OSM may contribute to fibrosis, neoangiogenesis, and the cytokine storm observed in JAK2 V617F+ MPN, suggesting that OSM could serve as a novel therapeutic target molecule in these neoplasms. IMR90 cells were treated with a single dose of rh Oncostatin M (10ng/ml).
2013-01-29 | E-GEOD-29655 | biostudies-arrayexpress
Project description:The JAK2 mutation V617F is detectable in a majority of patients with Ph-negative myeloproliferative neoplasms (MPN). Enforced expression of JAK2 V617F in mice induces myeloproliferation and bone marrow (BM) fibrosis suggesting a causal role for the JAK2 mutant in the pathogenesis of MPN. However, little is known about mechanisms and effector molecules contributing to JAK2 V617F-induced myeloproliferation and fibrosis. Here we show that JAK2 V617F promotes expression of oncostatin M (OSM) in neoplastic myeloid cells. Correspondingly, OSM was found to be overexpressed in the BM and elevated in the serum of patients with JAK2 V617F+ MPN. In addition, OSM secreted by JAK2 V617F+ cells stimulated growth of fibroblasts and microvascular endothelial cells and induced the production of angiogenic and profibrogenic cytokines (HGF, VEGF, and SDF-1) in BM fibroblasts. All effects of MPN cell-derived OSM were blocked by a neutralizing anti-OSM antibody, whereas the production of OSM in MPN cells was effectively suppressed by a pharmacologic JAK2 inhibitor or RNAi-mediated knockdown of JAK2. In summary, JAK2 V617F-mediated upregulation of OSM may contribute to fibrosis, neoangiogenesis, and the cytokine storm observed in JAK2 V617F+ MPN, suggesting that OSM could serve as a novel therapeutic target molecule in these neoplasms.
2013-01-29 | GSE29655 | GEO
Project description:BaF3 were transfected with Jak2 V617F, Jak2 K539L or Mpl W515L, shotgun proteomic analysis with iTRAQ was performed
2016-05-26 | PXD002782 | Pride
Project description:The activation of PD-1 (Programmed Death receptor-1) on T cells can cause T cell exhaustion and immune tolerance. Some tumors up-regulate the expression of the ligand of PD-1, namely PD-L1 (Programmed Death Receptor-Ligand 1), thus preventing anti-tumor immune response and promoting immune-escape. Previous studies have shown that JAK2 (Janus Kinase 2) signaling can promote PD-L1 expression in Hodgkin Lymphoma. In Myeloproliferative Neoplasms (MPN), JAK2 is frequently characterized by the the presence of the point-mutation V617F, which leads to its constitutive activation and to uncontrolled cell proliferation and survival. Accordingly, tumor cell lines expressing JAK2 V617F express higher levels of PD-L1 as compared to tumor cell lines negative for such mutations. In this experiment, we transfected BaF3 cells with a vector (plasmid for Murine Stem Cell Virus) containing the gene for JAK2 with the point-mutation V617F. As control, we used BaF3 cells transfected with the same vector, but without the gene for JAK2 V617F (empty vector). Both the cell lines (with/without JAK2 V617F) were co-cultured with primary murine T cells. When co-cultured with BaF3 cells expressing JAK2 V617F, T cells upregulated genes connected to senescence pathways, showed increased apoptosis, less cytokine production, and displayed other forms of dysfunction which can be associated with the activation of PD-1.
2018-12-01 | E-MTAB-5028 | biostudies-arrayexpress
Project description:To study therapeutic impacts of α-KG on MPN, cKIT+ cells from JAK2 V617F CD45.2 C57BL/6J mice were isolated and transplanted into irradiated CD45.1 C57BL/6J mice. Two weeks after transplant, mice were randomly grouped and supplemented with regular water or 1% α-KG in drinking water daily for 6 weeks. Bone marrow samples were collected for bulk RNA-seq analysis.
2024-01-01 | GSE244587 | GEO
Project description:Transcriptional profiling of transformed Ba/F3 cells by myeloproliferative neoplasm-associated JAK2 V617F mutant comparing control Ba/F3 cells expressing wild type JAK2.
2013-10-31 | GSE34239 | GEO
Project description:In this dataset, we determine the global gene expression in human induced pluripotent stem (iPS) cell-derived CD61+ megakaryocytes carrying homozygous JAK2 V617F mutation or the JAK2 wildtype gene.
2024-01-25 | GSE228092 | GEO