Endothelial JAK2V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm

Castiglione, Melissa; Jiang, Yaping; Mazzeo, Christopher; Lee, Sandy; Chen, Juei‐Suei; Kaushansky, Kenneth; Yin, Wei; Lin, Richard Z.; Zheng, Haoyi; Zhan, Huichun

doi:10.1111/jth.15095

Cited by 28 publications

(35 citation statements)

References 80 publications

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“…The possible association of this condition with MPN has not been explored, and any etiological relationship remains unclear. Given the recent evidence that MPN affects vascular endothelial cells and triggers atherosclerosis [22][23][24], we included the condition in the pool of thrombotic vascular events. Unlike our findings regarding thrombotic events, the incidence and pattern of hemorrhagic events were similar to those described in previous reports.…”

Section: Discussionmentioning

confidence: 99%

Thrombotic and hemorrhagic events in 2016 World Health Organization-defined Philadelphia-negative myeloproliferative neoplasm

Song

Yeon

Lee

et al. 2021

Korean J Intern Med

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Background/Aims: Recent changes in the diagnostic criteria for myeloproliferative neoplasms (MPNs) and increasing patient numbers necessitate updating of the data on vascular events in patients with such disorders. Methods: In this single-center study, thrombotic and hemorrhagic events were retrospectively analyzed in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or PMF, based on the 2016 World Health Organization diagnostic criteria. Results: Of a total of 335 consecutive patients (139 ET, 42 pre-PMF, 124 PV, and 30 PMF patients; 192 males and 143 females) of median age 64 years (range, 15 to 91), 112 (33.4%) experienced a total of 126 thrombotic events before diagnosis, at the time of diagnosis, or during follow-up over a median of 4.6 years (range, 0.1 to 26.5). Cerebrovascular thrombosis (18.8%) was the most common initial event, followed by coronary heart disease (10.1%) and splanchnic (1.5%) and peripheral thrombosis (1.5%). Arterial thrombosis was more common than venous thrombosis (31.3% vs. 2.1%, respectively; p = 0.001). Thrombosis was most frequent in PV patients (39.5%), followed by patients with pre-PMF (38.1%), ET (30.9%), and PMF (13.3%). Of the 112 patients who experienced thromboses, 53 (47%) and 39 (33.9%) had thrombotic events before and at the time of MPN diagnosis, respectively. Twenty-seven patients (8.1%) experienced 29 hemorrhagic events, of which gastrointestinal bleeding (n = 20) was the most common. Conclusions: Most thrombotic events occurred before or at the time of diagnosis, and the prevalence of arterial thrombosis was markedly higher than that of venous thrombosis in patients with MPN.

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Section: Discussionmentioning

confidence: 99%

Thrombotic and hemorrhagic events in 2016 World Health Organization-defined Philadelphia-negative myeloproliferative neoplasm

Song

Yeon

Lee

et al. 2021

Korean J Intern Med

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“…Similarly, Castiglione et al demonstrated that the MPN phenotype in Tie2-Cre/FF1 mice, that express JAK2 V617F in both hematopoietic and ECs is associated with thrombosis, vasculopathy, and cardiomyopathy but that this phenotype is lost if JAK2 V617F expression is restricted only to hematopoietic cells without mutated ECs, suggesting a critical role for mutated ECs in the pro-thrombotic phenotype. Indeed, JAK2 V617F expressing ECs displayed a pro-adhesive, pro-inflammatory, and vasculopathic phenotype [110]. Guy et al…”

Section: Endotheliummentioning

confidence: 99%

“…Endothelial cells (ECs) carrying the JAK2 V617F mutation [108] express a pro-inflammatory transcriptome with increased expression of vWF and P-selectin and increased adhesiveness of leukocytes to ECs [109]. They also display a pro-adhesive, pro-inflammatory, vasculopathic phenotype [110] due to increased endothelial P-selectin exposure, secondary to degranulation of Weibel-Palade bodies. Thrombo-inflammation-Increased levels of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8 and tissue necrosis factor (TNF)-α [112,113], as well as increased inflammatory markers such as C-reactive protein (CRP) and pentraxin-3 [114,115] are found in patients with MPNs.…”

Section: Covid-19 Mpns and Thrombosis-(mechanistic) Lessons Learned From The Pandemicmentioning

confidence: 99%

Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches?

Wolach

Abulafia

2021

Hemato

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Despite recent advances in diagnosis and therapy, arterial and venous thrombosis remain a major cause of morbidity and mortality in Philadelphia-negative myeloproliferative neoplasms (MPNs). Preventing and treating arterial and venous thrombosis represent one of the major goals in MPNs. The prothrombotic phenotype of MPNs is the result of a complex interplay between several components. Neutrophils, platelets, red blood cells (RBCs) and endothelial cells assume an activated phenotype in MPNs and undergo morphologic and metabolic changes that render these cells prothrombotic. These changes are in part the result of alterations induced by MPN initiating, driving mutations as well as the effect of extrinsic factors that stem from cell interactions as well as the inflammatory environment and rheological properties that characterize MPNs. In this review, we address current management issues in MPNs and provide an update on recent understanding of the pathogenesis of thrombosis in MPNs. We also address how lessons learned from other thrombo-inflammatory conditions can further inform and improve management of thrombosis in MPNs. Based on the above data and recent discoveries and developments, we discuss potential novel targets and therapeutic approaches to tackle the challenge of thrombosis in MPNs.

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“…Left ventricular (LV) dimensions at end-systole and end-diastole and fractional shortening (percent change in LV diameter normalized to end-diastole) were measured from the parasternal long-axis view using linear measurements of the LV at the level of the mitral leaflet tips during diastole. LV ejection fraction (EF), volume, and mass are measured and calculated using standard formulas for the evaluation of LV systolic function 32,36 .…”

Section: Transthoracic Echocardiographymentioning

confidence: 99%

“…The mutation can also be detected in 60-80% of EC progenitors derived from the hematopoietic lineage and, in some reports based on in vitro culture assays, in endothelial colony-forming cells from patients with MPNs [22][23][24][25][26] . Previously, we reported that the JAK2V617F-bearing vascular endothelium promotes the expansion of the JAK2V617F mutant HSPCs in preference to wild-type HSPCs [27][28][29][30][31] and contributes to the development of cardiovascular complications 32 in a murine model of MPN. In the present study, we investigated how MPN progresses in the JAK2V617F-bearing vascular niche during aging.…”

Section: Introductionmentioning

confidence: 99%

A murine model with JAK2V617F expression in both hematopoietic cells and vascular endothelial cells recapitulates the key features of human myeloproliferative neoplasm

Zhang

Yeware

Lee

et al. 2021

Preprint

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The myeloproliferative neoplasms (MPNs) are characterized by an expansion of the neoplastic hematopoietic stem/progenitor cells (HSPC) and an increased risk of cardiovascular complications. The acquired kinase mutation JAK2V617F is present in hematopoietic cells in a majority of patients with MPNs. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can also be detected in patients with MPNs. In this study, we show that a murine model with both JAK2V617F-bearing hematopoietic cells and JAK2V617F bearing vascular ECs recapitulated all the key features of the human MPN disease, which include disease transformation from essential thrombocythemia to myelofibrosis, extramedullary splenic hematopoiesis, and spontaneous cardiovascular complications. During aging and MPN disease progression, there was a loss of both HSPC number and HSPC function in the marrow while the neoplastic hematopoiesis was relatively maintained in the spleen, mimicking the advanced phases of human MPN disease. Different vascular niche of the marrow and spleen could contribute to the different JAK2V617F mutant stem cell functions we have observed in this JAK2V617F-positive murine model. Compared to other MPN murine models reported so far, our studies demonstrate that endothelial dysfunction plays an important role in both the hematologic and cardiovascular abnormalities of MPN.

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Endothelial JAK2V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 28 publications

References 80 publications

Thrombotic and hemorrhagic events in 2016 World Health Organization-defined Philadelphia-negative myeloproliferative neoplasm

Thrombotic and hemorrhagic events in 2016 World Health Organization-defined Philadelphia-negative myeloproliferative neoplasm

Can Novel Insights into the Pathogenesis of Myeloproliferative Neoplasm-Related Thrombosis Inform Novel Treatment Approaches?

A murine model with JAK2V617F expression in both hematopoietic cells and vascular endothelial cells recapitulates the key features of human myeloproliferative neoplasm

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