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Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F

ABSTRACT: Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F

PROVIDER: PRJNA1200665 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31781611_1.fastq.gz	Fastqsanger.gz
	SRR31781611_2.fastq.gz	Fastqsanger.gz
	SRR31781612_1.fastq.gz	Fastqsanger.gz
	SRR31781612_2.fastq.gz	Fastqsanger.gz
	SRR31781613_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F

Project description:Therapy with pegylated interferon alpha (pegIFNα) can induce a deep molecular response in a subset of patients with myeloproliferative neoplasms (MPN). Here we investigated the role of Socs2, a negative regulator of cytokine signaling, in modulating the response to pegIFNα in a JAK2-V617F mouse model of MPN. Deleting Socs2 in JAK2-V617F mice resulted in increased sensitivity to cytokines, without causing significant alterations in the MPN phenotype. When subjected to pegIFNα, the loss of Socs2 enhanced the depletion of JAK2-mutant hematopoietic stem cells (HSCs), evidenced by reduced chimerism in peripheral blood and bone marrow compared to vehicle controls. Additionally, pegIFNα-treated Socs2-deficient JAK2-mutant HSCs exhibited functional impairments in secondary transplantations, reflecting long-term detrimental decline of their stemness. These findings demonstrate that loss of Socs2 enhances the effectiveness of pegIFNα in depleting the JAK2-mutant HSC clone. In line with the genetic ablation of Socs2, the SOCS2 inhibitor MN714 combined with IFNα exhibited better efficacy than IFNα alone in reducing the output of CD34+ cells from PV patients in vitro. Targeting SOCS2 could therefore improve therapeutic responsiveness in MPN patients receiving interferon therapy.

2025-02-18 | GSE284784 | GEO

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

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predispose to myeloproliferative neoplasms

Project description:Genome-wide association study of JAK2 V617F negative myeloproliferative neoplasms consisting of 524 cases at stage 1

2015-02-20 | E-MTAB-3340 | 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

Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis

Project description:Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis

| PRJNA323924 | ENA

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

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

Complementary and countervailing actions of Jak2 and Ikk2 in hematopoiesis in mice

Project description:Hyperactivation of JAK2 kinase is a unifying feature of human Ph- myeloproliferative neoplasms (MPNs), most commonly due to the JAK2 V617F mutation. Mice harboring a homologous mutation in the Jak2 locus exhibit a phenotype resembling polycythemia vera. NFκB pathway hyperactivation is present in myeloid neoplasms, including MPNs, despite scarcity of mutations in NFκB pathway genes. To determine the impact of NFκB pathway hyperactivation in conjunction with Jak2 V617F, we utilized Ikk2 (Ikk2-CA) mice. Pan-hematopoietic Ikk2-CA alone produced depletion of hematopoietic stem cells and B cells. When combined with the Jak2 V617F mutation, Ikk2-CA rescued the polycythemia vera phenotype of Jak2 V617F. Likewise, Jak2 V617F ameliorated defects in hematopoiesis produced by Ikk2-CA. Single-cell RNA sequencing of hematopoietic stem and progenitor cells revealed multiple genes antagonistically regulated by Jak2 and Ikk2, including subsets whose expression was altered by Jak2 V617F and/or Ikk2-CA but partly or fully rectified in the double mutant. We hypothesize that Jak2 promotes hematopoietic stem cell population self-renewal, whereas Ikk2 promotes myeloid lineage differentiation, and biases cell fates at several branch points in hematopoiesis. Jak2 and Ikk2 both regulate multiple genes affecting myeloid maturation and cell death. Therefore, the presence of dual Jak2 and NFκB hyperactivation may present neomorphic therapeutic vulnerabilities in myeloid neoplasms.

2025-04-07 | GSE263101 | GEO

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

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

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