Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome

Sano, Soichi; Oshima, Kosei; Wang, Ying; MacLauchlan, Susan; Katanasaka, Yasufumi; Sano, Miho; Zuriaga, María A.; Yoshiyama, Minoru; Goukassian, David A.; Cooper, Matthew A.; Fuster, José J.; Walsh, Kenneth

doi:10.1016/j.jacc.2017.12.037

Cited by 492 publications

(545 citation statements)

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“…TET2-or JAK2V617F-induced CHIP), in which cardiovascular diseases (e.g. atherosclerosis, heart failure) only develop when the mice are challenged with additional risk factors, 6,[31][32][33][34] our Tie2FF1 mice (with both JAK2V617F-mutant blood cells and JAK2V617Fmutant vascular ECs) develop spontaneous DCM when fed on regular chow diet. In contrast, a chimeric murine model with JAK2V617F-mutant blood cells and wild-type vascular ECs did not develop any sign of cardiac dysfunction during 8-month follow up despite the development of myeloproliferative phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…TET2, JAK2V617F) when the mice are challenged with additional risk factors (e.g. high-fat/high-cholesterol diet, 6,31 surgical ligation/constriction of the coronary artery or aorta, 32,33 or hyperlipidemia genetic background via knocking-out of low-density lipoprotein receptor 34 ). In contrast, our Tie2FF1 mice, in which the JAK2V617F mutation is expressed in both blood cells and vascular ECs, develop spontaneous heart failure with increased risk of sudden death when fed on a regular chow diet.…”

Section: Jak2v617f-mutant Ecs Are Required To Develop the Cardiovascumentioning

confidence: 99%

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

Castiglione

Mazzeo

Jiang

et al. 2019

Preprint

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Rational: The myeloproliferative neoplasms (MPNs) are clonal hematological malignancies characterized by hematopoietic stem cell expansion and overproduction of mature blood cells. Cardiovascular complications are the leading cause of morbidity and mortality in patients with MPNs. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for cardiovascular dysfunction in MPNs are not fully understood, limiting the effectiveness of current treatment. Objective: Vascular endothelial cells (ECs) play critical roles in the regulation of hemostasis and thrombosis. ECs carrying the JAK2V617F mutation can be detected in patients with MPNs. The goal of this study was to test the hypothesis that the JAK2V617F mutation alters endothelial function to promote cardiovascular complications in patients with MPNs. Methods and Results: We employed murine models of MPN in which the JAK2V617F mutation is expressed in specific cell lineages. When JAK2V617F is expressed in both blood cells and vascular ECs, the mice developed MPN and spontaneous, age-related dilated cardiomyopathy with an increased risk of sudden death as well as a prothrombotic and vasculopathy phenotype on histology evaluation. We showed that JAK2V617F-mutant ECs are required for this cardiovascular disease phenotype and the mutation can alter endothelial cell function. Finally, in a more therapeutically oriented approach, we demonstrated that transplantation with wild-type donor marrow cells can improve cardiac function by reversing the left ventricle remodeling process in this JAK2V617F-positive MPN murine model. Conclusions: These findings suggest that the JAK2V617F mutation alters vascular endothelial function to promote cardiovascular complications in MPNs. Therefore, targeting the MPN vasculature represents a promising new therapeutic strategy for patients with MPNs.

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Section: Discussionmentioning

confidence: 99%

Section: Jak2v617f-mutant Ecs Are Required To Develop the Cardiovascumentioning

confidence: 99%

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

Castiglione

Mazzeo

Jiang

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…94 In a murine model, Tet2-deficient macrophages contribute to vascular inflammation and accelerated atherosclerosis through increased NLRP3 inflammasome-mediated secretion of the pro-inflammatory cytokine interleukin-1β. 95,96 Similarly, Jak2 mutated macrophages display increased production of pro-inflammatory cytokines and chemokines and inflammasome activation, and erythrocytes generated from Jak2mutated precursors are more susceptible to erythrophagocytosis by macrophages. 97 These findings provide a mechanistic link between CH and the development of atherosclerotic disease, but importantly also point toward potential therapeutic interventions, for example, through antibodies targeting interleukin-1β signaling.…”

Section: Ch and Cardiovascular Diseasementioning

confidence: 99%

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease‐specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH‐related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non‐hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.

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“…Therefore, attempts to find therapeutic targets that allow for adequate collagen expression while avoiding excessive fibrosis have been largely unsuccessful. For example, although increased levels of interleukin-1 (IL1) have been linked to fibrosis and diminished cardiac index post-MI[6], blocking IL1 post-MI does not consistently improve healing and is actually associated with an increased risk of secondary MI[7, 8].…”

Section: Introductionmentioning

confidence: 99%

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

Zeigler

Nelson

Chandrabhatla

et al. 2019

Preprint

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2The fibroblast is a key mediator of wound healing in the heart and other organs, yet how 2 3 it integrates multiple time-dependent paracrine signals to control extracellular matrix 2 4 synthesis has been difficult to study in vivo. Here, we extended a computational model to 2 5 simulate the dynamics of fibroblast signaling and fibrosis after myocardial infarction in 2 6 response to time-dependent data for nine paracrine stimuli. This computational model 2 7was validated against dynamic collagen expression and collagen area fraction data from 2 8 post-infarction rat hearts. The model predicted that while many features of the fibroblast 2 9 phenotype at inflammatory or maturation phases of healing could be recapitulated by 3 0 single static paracrine stimuli (interleukin-1 and angiotensin-II, respectively), mimicking 3 1 of the proliferative phase required paired stimuli (e.g. TGFβ and angiotensin-II). Virtual 3 2 overexpression screens with static cytokine pairs and after myocardial infarction 3 3 predicted phase-specific regulators of collagen expression. Several regulators increased 3 4 (Smad3) or decreased (Smad7, protein kinase G) collagen expression specifically in the 3 5 proliferative phase. NADPH oxidase overexpression sustained collagen expression from 3 6 proliferative to maturation phases, driven by TGFβ and endothelin positive feedback 3 7 loops. Interleukin-1 overexpression suppressed collagen via NFκB and BAMBI (BMP 3 8 and activin membrane-bound inhibitor) incoherent feedforward loops, but it then later 3 9 sustained collagen expression due to the TGFβ positive feedback loop. These model-4 0 based predictions reveal network mechanisms by which the dynamics of paracrine stimuli 4 1 and interacting signaling pathways drive the progression of fibroblast phenotypes and 4 2 fibrosis after myocardial infarction. 4 3 4 4 4 5Wound healing is a complex process that involves a dynamic interplay between 4 6 inflammatory and proliferative signaling. This process is especially important following 4 7 injury to the heart, where cardiomyocytes are unable to regenerate. Scar formation and 4 8 the preservation of viable heart muscle are important for continued cardiac function[1]. 4 9 8 1 understanding how fibroblasts respond during the different phases of wound healing 8 2 could identify mechanisms by which fibrosis develops in other organs. 8 3 Myocardial infarct healing is notoriously difficult to investigate because it 8 4 involves many dynamic and interacting signaling processes. Fibroblasts are particularly 8 5 difficult to study in situ during wound healing because they can differentiate from many 8 6 different cell types and there is no clear consensus on fibroblast markers[20].8 7Computational modeling has been a useful method for investigating complex dynamic 8 8 processes in many areas of biology. Although models have been constructed to study the 8 9 wound healing process post-MI[21], no such model has yet been applied to study 9 0 5 fibroblast intracellular signaling and phenotypic changes during m...

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Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome

Cited by 492 publications

References 47 publications

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

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

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Computational Model Predicts Paracrine and Intracellular Drivers of Fibroblast Phenotype After Myocardial Infarction

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