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AG221 and Ruxolitinib Treatment Effects on LSKs in IDH2-R140Q JAK2-V617F Transplant Recipients

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE95771 | GEO | 2018/02/22

REPOSITORIES: GEO

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Mus musculus

Project description:AG221 and Ruxolitinib Treatment Effects on LSKs in IDH2-R140Q JAK2-V617F Transplant Recipients

| PRJNA378381 | ENA

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

Gene expression profile at single cell level of phenotypic LT-HSCs from single-mutant JAK2 V617F and double mutant JAK2 V617F;Dnmt3a-/- mice

Project description:We investigated if Dnmt3a loss leads to alterations in JAK2 V617F LT-HSCs heterogenity and expression profile using single-cell RNA sequencing.

2024-03-29 | GSE225918 | GEO

Identification of potential of new therapeutic approaches for JAK2 V617F mutant patients

Project description:n patients with PMF, excessive secretion of inflammatory cytokines results in fibrotic changes in bone marrow and diminishes the quality of life of the affected patients due to systemic symptoms long-term ruxolitinib therapy may reverse or markedly delay BM fibrosis progression in advanced MF suggests kavasincha 2018

2023-05-18 | PXD027250 | Pride

Hematopoietic Stem Cell Heterogeneity in JAK2 V617F+ Essential Thrombocythemia

Project description:In this study, we explored the transcriptome of hematopoietic stem cells (HSCs) and megakaryocyte-erythroid progenitors (MEPs) in JAK2 V617F+ PV and ET and found that distinctive gene expression patterns within MPN subtypes begin at the HSC stage. HSCs from ET exhibited prominent megakaryocyte (Mk)-lineage priming. The differentially expressed genes (DEGs) indicated that cellular processes and signaling pathways in HSCs and MEPs from healthy donors (HDs), PV and ET patients are differentially modulated

2021-02-22 | GSE111410 | GEO

Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells.

Project description: Not available

| S-EPMC7072561 | biostudies-literature

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

Project description:We present cell line SET-2 as potential model system for DNA methylation analysis. This cell line was established from a patient with essential thrombocythemia at megakaryoblastic transformation and carries the JAK2 V617F mutation. Cell line SET-2 carries the DNMT3A R882H mutation, recurrent in cytogenetically normal AML.

2019-11-13 | E-MTAB-8323 | biostudies-arrayexpress

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

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

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

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. Two-condition experiment, WT cells vs. VF cells. One replicate per array.

2013-10-31 | E-GEOD-34239 | biostudies-arrayexpress

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.

2018-12-01 | E-MTAB-5028 | biostudies-arrayexpress

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