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Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228092 | GEO | 2024/01/25

REPOSITORIES: GEO

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Bulk RNAseq of megakaryocytes and Lin- cells of mice with Srsf2-P95H mutation, Jak2-V617F mutation, both, or none

Project description:We performed bulk RNAseq of sorted megakaryocytes and subsequent Lin- cells to study the impact of the combination of Jak2 V617F mutations and Srsf2 P95H mutations

2023-07-01 | E-MTAB-11960 | biostudies-arrayexpress

Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche

Project description:Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche

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Effects of the treatment with pegIFNa, Azacytidine or pegIFNa+Azacytidine in LT-HSCs from JAK2-V617F MPN mice or JAK2-V617F;Dnmt3a-KO MPN mice.

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

CALR frameshift mutations accelerate maturation of megakaryocytes in MPN patient-derived iPS cells

Project description:In this dataset, we compare the gene expression data of induced pluripotent stem (iPS) cell-derived CD61+ megakaryocytes carrying heterozygous or homozygous Calreticulin (CALR) ins5 mutations or the CALR wildtype gene.

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Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche.

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Analysis of mouse T cell transcription profile after co-culture with BaF3 cells with or without the oncogenic point mutation JAK2 V617F

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.

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Murine Ba/F3 Cells: Ba/F3 cells expressing wild type JAK2 (WT cells) vs. Ba/F3 cells expressing JAK2 V617F mutant (VF cells)

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DNMT3A R882H mutation in JAK2 V617F AML cell line SET-2

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