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Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

ABSTRACT: Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

PROVIDER: PRJNA1107178 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28873015_1.fastq.gz	Fastqsanger.gz
	SRR28873015_2.fastq.gz	Fastqsanger.gz
	SRR28873016_1.fastq.gz	Fastqsanger.gz
	SRR28873016_2.fastq.gz	Fastqsanger.gz
	SRR28873017_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

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

Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

2024-05-02 | GSE266434 | GEO

Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

Project description:Decoding Endothelial MPL and JAK2V617F Mutation: Insight into Cardiovascular Dysfunction in Myeloproliferative Neoplasms

| PRJNA1108413 | ENA

Pathophysiology of arterial cardiovascular events in patients with JAK2V617F myeloproliferative neoplasms

Project description:Cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms. Their mechanisms are poorly understood. To investigate the role of microvesicles in these events, we performed a proteomic analysis of microvesicles derived from red blood cells from mice with a myeloproliferative neoplasms (Jak2V617F Flex/WT ;VE-cadherin-Cre) vs. littermate controls.

2020-02-17 | PXD014451 | Pride

JAK2V617F Impairs Lymphoid Differentiation in Myeloproliferative Neoplasms

Project description:JAK2V617F Impairs Lymphoid Differentiation in Myeloproliferative Neoplasms

| PRJNA1122535 | ENA

JAK2V617F Impairs Lymphoid Differentiation in Myeloproliferative Neoplasms

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

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

Project description:Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

| PRJNA840908 | ENA

Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms

Project description:Janus kinases (JAKs) mediate cytokine signaling, cell growth and hematopoietic differentiation. Gain-of-function mutations activating JAK2 signaling are seen in the majority of myeloproliferative neoplasm (MPN) patients, most commonly due to the JAK2V617F driver allele. While clinically-approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic JAK inhibitor therapy in most patients. This has been postulated to be due to incomplete dependence on constitutive JAK/STAT signaling, alternative signaling pathways, and/or the presence of cooperating disease alleles; however we hypothesize this is due to the inability of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a Dre-rox/Cre-lox dual orthogonal recombinase system. Deletion of oncogenic Jak2V617F abrogates the MPN disease phenotype, induces mutant-specific cell loss including in hematopoietic stem/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition. Furthermore, reversal of Jak2V617F in MPN cells with antecedent loss of Tet2 abrogates the MPN phenotype and inhibits mutant stem cell persistence suggesting cooperating epigenetic-modifying alleles do not alter dependence on mutant JAK/STAT signaling. Our results suggest that mutant-specific inhibition of JAK2V617F represents the best therapeutic approach for JAK2V617F-mutant MPN and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.

2022-05-25 | GSE203464 | GEO

Myelodysplastic/myeloproliferative neoplasms

Project description:This SuperSeries is composed of the following subset Series: GSE21948: High Density custom Agilent 44K CGH array analysis of 7q and TET2 region in myelodysplastic/myeloproliferative neoplasms GSE21990: Affymetrix SNP 6.0 array data for myelodysplastic/myeloproliferative neoplasms Refer to individual Series

2010-06-30 | E-GEOD-21991 | biostudies-arrayexpress

Quantitative Analysis of JAK2V617F/+ Plek2+/+ and JAK2V617F/+ Plek2-/- erythroblast and hematopoietic stem cells/ progenitor cells Transcriptomes

Project description:V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2V617F knockin mice. To reveal the role of Plek2 in the pathogenesis of JAK2V617F-induced MPNs and the detail mechanisms of its rescue, we performed RNA sequencing to analyze the gene expression profiles change between JAK2V617F/+ Plek2+/+ and JAK2V617F/+ Plek2-/- erythroblasts and hematopoietic stem/progenitor cells.

2019-04-11 | GSE97658 | GEO

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