JAK2V617F-dependent clonal hematopoiesis drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
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ABSTRACT:
PROVIDER: PRJNA890296 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21896000_1.fastq.gz | Fastqsanger.gz | |||
| SRR21896000_2.fastq.gz | Fastqsanger.gz | |||
| SRR21896001_1.fastq.gz | Fastqsanger.gz | |||
| SRR21896001_2.fastq.gz | Fastqsanger.gz | |||
| SRR21896002_1.fastq.gz | Fastqsanger.gz |
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Project description:In order to understand the mechanisms responsible for lethal JAK2V617F-dependent aortic disease, we performed RNA sequencing in the aorta of 7-week old Jak2V617F HC-EC and control Jak2WT mice
2022-10-20 | GSE215455 | GEO
Project description:JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
2022-10-26 | GSE214880 | GEO
Project description:JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
| S-EPMC9633755 | biostudies-literature
Project description:Myeloproliferative neoplasms (MPNs) arise via the acquisition of a driver mutation in a single hematopoietic stem cell (HSC), often decades prior to the development of a clinical phenotype. The most common MPN driver mutation, JAK2V617F, activates aberrant JAK/STAT signaling via cytokine receptors critical for myelopoiesis. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production and contributes to lymphopenia in patients with MPNs and leades to elevated neutrophil-to-lymphocyte ratio (NLR), which is predictive of disease-related complications including thrombosis and mortality. We conducted this study to learn how hematopoiesis from the JAK2V617F clone affects lymphopoiesis in patients with MPNs. Although myeloid proliferation via aberrant JAK2 signaling is the most apparent mechanistic link between JAK2V617F and MPN phenotypes, our findings demonstrate that impaired lymphoid differentiation is an additional feature of JAK2V617F hematopoiesis, leading to the rarity of JAK2V617F lymphocytes despite the dominance of JAK2V617F HSCs in patients with MPNs. The combination of prolific myelopoiesis and defective lymphopoiesis from the JAK2V617F clone is a potential connection between MPN pathology and the surrogate markers, including NLR and lymphopenia, which hold prognostic significance. Based on our data, we speculate that, defective JAK2V617F lymphopoiesis and the consequent increased burden of lymphopoiesis from residual normal HSC clones drives the appearance of abnormal lymphocyte subsets, lymphoproliferative disease or T cell exhaustion in MPNs. Further study of MPN lymphopoiesis provides an opportunity to define the immune deficits underlying the myriad complications that affect patients with MPNs.
2024-09-01 | GSE269568 | GEO
Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-02 | GSE266434 | GEO
Project description:Background: Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential (CHIP) face a significantly elevated risk of cardiovascular diseases (CVDs). Endothelial cells (ECs) carrying the JAK2V617F mutation have been detected in many MPN patients. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in MPN patients. Methods: We investigated the impact of endothelial JAK2V617F mutation on CVD development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Results and Conclusions: Our investigations revealed that JAK2V617F mutant ECs promote CVDs by impairing endothelial function and undergoing endothelial-to-mesenchymal transition (EndMT). Importantly, we discovered that inhibiting the endothelial thrombopoietin receptor MPL suppressed JAK2V617F-induced EndMT and prevented cardiovascular dysfunction caused by mutant ECs. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function, rendering it a promising therapeutic target for preventing or ameliorating cardiovascular complications in patients with MPNs.
2024-05-20 | GSE266848 | GEO
Project description:Interferon alpha (IFNa) is an effective treatment for patients with myeloproliferative neoplasms (MPN). In addition to inducing hematological responses in most MPN patients, IFNa reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNa on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNa on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNa treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNa treatment induces cell-cycle activation of Jak2V617F mutant long-term hematopoietic stem cells (LT-HSC) and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNa on Jak2V617F mutant and normal hematopoiesis and suggest that IFNa achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN, by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNa and targeting the proliferating downstream progeny with JAK2-inhibitors or cytotoxic chemotherapy.
2013-03-09 | GSE44961 | GEO
Project description:IL-27 receptor signaling regulated stress hematopoiesis drives Abdominal Aortic Aneurysm development
| PRJNA533084 | ENA
Project description:In order to explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an up-regulation of inflammatory genes related to neutrophil activation and thrombosis, and the other one with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signaling pathway, presented a lower expression,. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways besides JAK-STAT might be implicated in the pathophysiology of JAK2V617F-negative ET patients. Keywords: Disease state analysis
2008-05-19 | GSE11003 | GEO
Project description:Recent studies have shown that both TET2 mutation and JAK2V617F mutation are frequent in myeloproliferative neoplasms patients. The pathophysiological roles of each mutation have been elucidated in murine models, but the cooperative effect of the two mutations has not been elucidated yet. In this study, we examined the function of the cooperative effect of loss-of-TET2 function and JAK2V617F mutation in murine hematopoiesis.
2014-10-16 | GSE62302 | GEO