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Expression profiling of hematopoietic stem cells/progenitors from young (3 months) and old (12 months) homozygous Jak2 R1063H mice and wild-type controls

ABSTRACT: While familial and sporadic forms of myeloproliferative neoplasms (MPNs) have long been recognized, emerging evidence implicates germline variations, in predisposing individuals to JAK2 V617F-positive myeloproliferative neoplasms (MPN). Understanding the role of genetic variants, such as the JAK2 germline mutations, in MPN susceptibility, along with the contribution to disease pathogenesis, is crucial for elucidating the underlying mechanisms driving MPN development and progression. To study the biology of germline JAK2 R1063H mutation in more detail, we edited the endogenous Jak2 locus by CRISPR/Cas9 technology. We performed expression gene profiling of young (3 months) and old (12 months) HSC (defined as Lin-, Sca1+/ckithigh, CD150high/CD48low) and LK cells (defined as Lin-, Sca1-/ckithigh).

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Jan Kubovčiak

PROVIDER: E-MTAB-14686 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression profiling of platelets from young (3 months) homozygous Jak2 R1063H mice and wild-type controls

Project description:Patients with myeloproliferative neoplasms (MPN), are known to be at an elevated risk for thrombosis but the mechanism for MPN-related coagulation activation is not yet fully characterized. While increased hematocrit has been re-evaluated as a contributing factor, additional mechanisms such as chronic inflammation and a pro-adhesive phenotype associated with increased endothelial P-selectin expression have been elucidated in MPN thrombogenesis. Additionally, non-myeloid inflammatory cells, red blood cells and platelets may also contribute to increased vascular resistance and promote thrombosis. However, the mechanism of thrombosis associated with JAK2 germline mutations has not been described. We performed expression gene profiling of platelets isolated from young (3 months) homozygous Jak2 R1063H mice and wild-type controls.

2025-08-22 | E-MTAB-14685 | biostudies-arrayexpress

Expression profiling of endothelial cells from old (12 months) and very old (18 months) homozygous Jak2 R1063H mice and wild-type controls

Project description:To investigate the biological role of the germline JAK2-R1063H mutation, which may contribute to susceptibility and pathogenesis of myeloproliferative neoplasms, we generated a mouse model by introducing the R1063H variant into the endogenous Jak2 locus using CRISPR/Cas9 genome editing. This model allowed us to explore not only hematopoietic but also non-hematopoietic compartments potentially affected by the mutation. Given the ongoing debate regarding the presence and functional impact of somatic JAK2-V617F in endothelial cells — and their possible involvement in thrombotic complications — we specifically examined whether Jak2-R1063H in endothelial cells drives similar pathogenic phenotype. Therefore, we isolated lung endothelial cells (CD45⁻/CD31⁺) from 12- and 18-month-old Jak2-R1063H and wild-type mice and conducted gene expression profiling.

2025-08-22 | E-MTAB-15355 | biostudies-arrayexpress

Oncostatin M effects in IMR90 cells

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

Germline duplication of ATG2B and GSKIP predisposes to familial essential thrombocythemia rapidly progressing to acute leukemia

Project description:No major predisposing gene for familial myeloproliferative neoplasms (MPN) has been identified. Here, we demonstrate that the autosomal dominant transmission of a 700 kb duplication in four geographically-related families predisposes to MPN rapidly progressing to acute leukemia. Using induced pluripotent stem and primary cells to explore hematopoietic differentiation, we demonstrate that overexpressed ATG2B and GSKIP enhance hematopoietic progenitor differentiation, including megakaryocytic through increasing their sensitivity to TPO. ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication changes the fitness of cells harboring signaling mutations and increases the probability of disease development.

2015-08-05 | GSE67938 | GEO

Development of resistance to type II JAK2 inhibition in MPN depends on AXL kinase and is targetable

Project description:Purpose: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Since clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.Methods: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC-/RNA-sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.Results: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NSG mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Since inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL-MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL-MAPK.Conclusions: We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN

2023-11-07 | PXD039419 | Pride

Oncostatin M effects in IMR90 cells

2013-01-29 | GSE29655 | GEO

Germline duplication of ATG2B and GSKIP predisposes to familial essential thrombocythemia rapidly progressing to acute leukemia

2015-08-05 | E-GEOD-67938 | biostudies-arrayexpress

JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones

Project description:Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication as it dramatically worsens disease prognosis. While sAML transformation is classically linked to MPN clones acquiring additional mutations, the absence of JAK2V617F in sAML cases originating from JAK2-mutant MPNs suggests alternative mechanisms. Utilizing patient samples and in vivo modeling, we establish that sAML clones can emerge independently of JAK2-mutant cells. These leukemic clones undergo positive selection in the pro-inflammatory MPN environment leading to their predominance in the hematopoietic system. Genetic and pharmacological inhibition of IL-12 and TNFa mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.

2026-02-24 | GSE308233 | GEO

DNA methylation profiles of JAK2-derived induced pluripotent stem cells (iPSC)

Project description:Myeloproliferative neoplasms (MPN) are a clonal hematological disease which harbors different driver mutations, including JAK2 V617F, and there is clear evidence that MPN is associated with aberrant DNA methylation (DNAm). However, it is unclear whether the driver mutation alone is sufficient to recapitulate the MPN phenotype and the global DNA methylation changes observed in patients. For this purpose, we utilized three established induced pluripotent stem cell (iPSC) clones carrying the JAK2 V617F mutation, both heterozygous and homozygous genotypes along with their wild type (WT) counterparts. These iPSCs were differentiated towards hematopoietic stem and progenitor differentiation (iHPCs) to capture the mutant phenotype. Genome wide methylation analysis of JAK2 mutated iPSCs and iHPCs showed no significant methylation differences compared to wild type cells. The iPSC model only partially recapitulated the DNAm changes observed in patients with JAK2 mutation, suggesting that epigenetic changes are not directly evoked by the driver mutation, but rather accumulate over the course of disease development.

2025-05-07 | GSE277890 | GEO

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

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