CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease

Sano, Soichi; Oshima, Kosei; Wang, Ying; Katanasaka, Yasufumi; Sano, Miho; Walsh, Kenneth

doi:10.1161/circresaha.118.313225

Cited by 326 publications

(339 citation statements)

References 22 publications

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“…Murine experiments demonstrated that mice with TET2-deficient HSC had larger atherosclerotic plaques [51,52]. This association appeared to be causal, as TET-2 inactivation in macrophages enhanced their pro-inflammatory activity upon antigen stimulation, with increased production of pro-inflammatory molecules IL-1β [49,[51][52][53], IL-6 [49,[51][52][53], as well as that of single C-X-C motif (CXC) chemokines CXCL1 [51] (a neutrophil chemotactic factor), CXCL2 [51] (also known as macrophage inflammatory protein 2-alpha), CXCL3 [51] (also known as macrophage inflammatory protein-2-beta) and platelet factor 4 [51] (involved in coagulation). TET2 regulates the transcription of pro-inflammatory factors such as IL-6 by binding to their gene promoters; once bound, TET2 recruits histone deacetylase (HDAC2) at this level, thereby facilitating histone deacetylation that terminates gene transcription [54].…”

Section: The Interplay Of Chip Immune Dysregulation and Cardiovascumentioning

confidence: 95%

“…A detailed discussion of these is beyond the scope of this review, and the authors direct the reader to an excellent updated overview of these models [48]. Briefly, here we will discuss evidence obtained using two mice models of hypertension-induced HFpEF, provoked by salty drinking water, unilateral nephrectomy, and chronic exposure to aldosterone (SAUNA) for 30 days [9], or by continuous angiotensin II (AT II) infusions administered via mini-osmotic pumps for 4 weeks [49]. A third model recapitulates HFpEF associated with aging, as older and senescent C57BL/6 mice present with mild left ventricular hypertrophy (LVH), interstitial fibrosis and diastolic dysfunction, but without hypertension (HTN) [9].…”

Section: Animal Models Of Hfpefmentioning

confidence: 99%

“…Another question focused on the role of TET2, and other CHIP-related mutations, in the development of heart failure (HF). To test this hypothesis, Sano et al evaluated two animal models of HFpEF, induced by AT II infusion [49] or TAC [53]. Mice transplanted with bone marrow derived from TET2 knockout (KO) mice developed a HFpEF phenotype, with cardiac hypertrophy, fibrosis, and increased cardiac macrophage infiltration [49,53].…”

Section: The Interplay Of Chip Immune Dysregulation and Cardiovascumentioning

confidence: 99%

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Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Sava

Pepine

March

2020

JCM

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Over 26 million people worldwide suffer from heart failure, a disease associated with a 1 year mortality rate of 22%. Half of these patients present heart failure with preserved ejection fraction (HFpEF), for which there is no available therapy to improve prognosis. HFpEF is strongly associated with aging, inflammation, and comorbid burden, which are thought to play causal roles in disease development. Mesenchymal stromal/stem cells (MSCs) have potent immunomodulatory actions and promote tissue healing, thus representing an attractive therapeutic option in HFpEF. In this review, we summarize recent data suggesting that a two-hit model of immune dysregulation lies at the heart of the HFpEF. A first hit is represented by genetic mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), which skew immune cells toward a pro-inflammatory phenotype, are associated with HFpEF development in animal models, and with immune dysregulation and risk of HF hospitalization in patients. A second hit is induced by cardiovascular risk factors, which cause subclinical cardiac dysfunction and production of danger signals. In mice, these attract proinflammatory macrophages, Th1 and Th17 cells into the myocardium, where they are required for the development of HFpEF. MSCs have been shown to reduce the pro-inflammatory activity of immune cell types involved in murine HFpEF in vitro, and to reduce myocardial fibrosis and improve diastolic function in vivo, thus they may efficiently target immune dysregulation in HFpEF and stop disease progression.

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Section: The Interplay Of Chip Immune Dysregulation and Cardiovascumentioning

confidence: 95%

Section: Animal Models Of Hfpefmentioning

confidence: 99%

Section: The Interplay Of Chip Immune Dysregulation and Cardiovascumentioning

confidence: 99%

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Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Sava

Pepine

March

2020

JCM

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“…Evidently, study of additional CHIP subtypes may uncover further intricacies of how CHIP hazardously intersects with the leading comorbidities in the developed world. For example, CRISPR-Cas9−edited models of CH for both Tet2 and Dnmt3a mutations yield similar effects on cardiac function, yet Dnmt3a mutants undergo limited expansion and exhibit different cytokine expression, suggesting a different means of achieving the same severity of disease [56]. DNMT3A mutations may cause further dysfunction in the realm of immunity and respirology.…”

Section: Ch As a Consequence Of Inflammationmentioning

confidence: 99%

Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity

Cook

Luo

Rauh

2020

Experimental Hematology

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Clonal hematopoiesis (CH) of indeterminate potential (CHIP), defined as the presence of a somatic mutation in the peripheral blood at a variant allele frequency (VAF) ≥2%, affects at least 10% of individuals older than 65, but low-VAF clones can be detected in 95% of individuals older than 50. CHIP associates with a wide range of comorbidities from atherosclerosis to pulmonary disease. A growing body of evidence, primarily from studies involving Tet2-knockout and stem cell transplant models of CH, suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities. Mutant leukocytes from animal models contribute to an inflammatory milieu that may confer a selective advantage to the clone, thus perpetuating a cycle of inflammation and expansion. Although it is unclear whether inflammation or expansion sets this cycle in motion, some evidence suggests that inflammation from infections or pre-existing comorbidities initiates this cycle. The pro-inflammatory phenotypes of macrophages from mutant clones and their contributions to disease are well characterized in murine models, but have not yet been confirmed in humans. Furthermore, the roles of other cell types that can carry mutations of CHIP are not fully understood. We propose a rationale for further investigation of neutrophils, other granulocytes and T, B, and NK cells as they may play a role in CHIP-associated comorbidities. As the understanding of CH has advanced, potential interventions, especially those targeting aberrant inflammation, have been proposed. We are hopeful that as studies continue to unravel the complex links between CHIP, inflammation, and leukocyte dysfunction, CHIP-related comorbidities may be more effectively managed.

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“…In this regard, TET2-deficiency results in an increased pro-inflammatory phenotype in murine macrophages, which may help to promote atherosclerosis (Abegunde, Buckstein, Wells, & Rauh, 2018;Cull, Snetsinger, Buckstein, Wells, & Rauh, 2017;Cull, Snetsinger, & Rauh, 2016). CH also alters cardiac repair by inflammatory pathways (Sano et al, 2018). Also in line with the inflammatory role of TET2, patients who underwent allogeneic bone marrow transplantation from donors with CH had an increased risk of chronic graft-versus-host disease (Frick et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

TET2 missense variants in human neoplasia. A proposal of structural and functional classification

Bussaglia¹,

Antón

Nomdedéu³

et al. 2019

Molec Gen & Gen Med

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Background The human TET2 gene plays a pivotal role in the epigenetic regulation of normal and malignant hematopoiesis. Somatic TET2 mutations have been repeatedly identified in age‐related clonal hematopoiesis and in myeloid neoplasms ranging from acute myeloid leukemia (AML) to myeloproliferative neoplasms. However, there have been no attempts to systematically explore the structural and functional consequences of the hundreds of TET2 missense variants reported to date. Methods We have sequenced the TET2 gene in 189 Spanish AML patients using Sanger sequencing and NGS protocols. Next, we performed a thorough bioinformatics analysis of TET2 protein and of the expected impact of all reported TET2 missense variants on protein structure and function, exploiting available structure‐and‐function information as well as 3D structure prediction tools. Results We have identified 38 TET2 allelic variants in the studied patients, including two frequent SNPs: p.G355D (10 cases) and p.I1762V (28 cases). Four of the detected mutations are reported here for the first time: c.122C>T (p.P41L), c.4535C>G (p.A1512G), c.4760A>G (p.D1587G), and c.5087A>T (p.Y1696F). We predict a complex multidomain architecture for the noncatalytic regions of TET2, and in particular the presence of well‐conserved α+β globular domains immediately preceding and following the actual catalytic unit. Further, we provide a rigorous interpretation of over 430 missense SNVs that affect the TET2 catalytic domain, and we hypothesize explanations for ~700 additional variants found within the regulatory regions of the protein. Finally, we propose a systematic classification of all missense mutants and SNPs reported to date into three major categories (severe, moderate, and mild), based on their predicted structural and functional impact. Conclusions The proposed classification of missense TET2 variants would help to assess their clinical impact on human neoplasia and may guide future structure‐and‐function investigations of TET family members.

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CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease

Cited by 326 publications

References 22 publications

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity

TET2 missense variants in human neoplasia. A proposal of structural and functional classification

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