Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice
Open accessAbstract
Faulty blood cells and heart disease: Recent studies have shown that elderly people's blood cells often harbor mutations in genes encoding certain epigenetic regulators. These mutations can lead to clonal expansion of the mutant blood cells, which increases the risk of blood cancers and cardiovascular disease. Fuster et al. generated a mouse model to investigate how one of these genes, Tet2 , affects atherosclerosis development (see the Perspective by Zhu et al. ). They found that the disease progressed more rapidly in mice transplanted with Tet2 -deficient bone marrow cells. This was due to increased secretion of interleukin-1β by Tet2 -deficient macrophages in a process that depended on the action of inflammasomes. Science , this issue p. 842 ; see also p. 798
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Inflammation has been shown to be a driver of Tet2-mutant clonal hematopoiesis.
“inflammation has been shown to be a driver of Tet2-mutant CH.”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Fuster et al., 2017
The paper reports the opposite causal direction: TET2 deficiency increases inflammatory cytokine production, while clonal expansion of TET2-deficient cells contributes to atherosclerosis. In the indexed passage labeled Abstract (page unavailable), NLRP3 inhibition reduced atherosclerosis but “did not affect the expansion of TET2-deficient cells”; it does not show inflammation driving that expansion. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCHIP-associated mutations alter the development and function of myeloid cells.
“As CHIP-associated mutations are known to alter the development and function of myeloid cells”
From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [11]
The indexed paper reports that TET2-deficient cells in mice show a myeloid differentiation bias and that TET2-deficient macrophages have altered inflammatory responses. This supports the claim for TET2, but the paper does not establish the same effects for CHIP-associated mutations generally. The indexed passages are labeled “Abstract”; no page numbers are supplied. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCH is associated with a significantly increased risk of all-cause mortality and particularly cardiovascular disease.
“This observation was repeated in subsequent reports which also added the significantly increased risk of all-cause mortality and particularly cardiovascular disease (CVD) [31,32].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
The indexed Abstract reports that clonal hematopoiesis correlates with increased atherosclerotic cardiovascular disease and describes human studies associating it with more CVD-related deaths. It does not report an association with all-cause mortality or establish statistical significance for those human associations. No page number is supplied in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLdlr−/− recipients of Tet2 knockout HSPCs have larger atherosclerotic plaques compared to control mice when fed a high-fat diet; the effect in heterozygous Tet2 knockout is relatively milder.
“The Ldlr−/− recipients of Tet2 knockout HSPCs had larger atherosclerotic plaques compared to the control mice when fed a high-fat diet; the effect in the heterozygous Tet2 knockout was relatively milder.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
The passage discussing atherogenesis (indexed under Abstract; page unavailable) reports that high-fat/high-cholesterol-fed Ldlr−/− mice receiving Tet2−/− bone marrow cells had 60% larger aortic-root plaques than wild-type controls. It also reports that Tet2+/− cells accelerated atherosclerosis, but describes slower cell-expansion kinetics—not a milder effect on plaque size—so the final comparison is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTet2 loss, including Tet2 heterozygous knockout, confers increased competitive repopulating capacity in Ldlr−/− recipients on a high-fat/high-cholesterol diet, notable both at mature cells and HSPC compartment in marrow.
“In murine models, Tet2 loss, including the more clinically relevant Tet2 heterozygous knockout state, confers increased competitive repopulating capacity in Ldlr−/− recipients on a high-fat/high-cholesterol diet notable both at the level of mature cells and the HSPC compartment in the marrow [31].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
The paper’s competitive-transplantation passages report expansion of Tet2−/− cells in Ldlr−/− recipients fed a high-fat/high-cholesterol diet, both among mature blood cells and in the marrow HSPC compartment (Abstract; Figs. 1 and S3). It also reports expansion of Tet2+/− cells, but describes slower kinetics and does not establish the claimed marrow-HSPC finding specifically for heterozygous cells (Abstract; Fig. S5). (LLM, conf=0.84)
Experimental — accuracy not yet measured
CHIP-associated mutations in myeloid cells promote inflammatory signaling and accelerate atherosclerosis, establishing a causal link between somatic mosaicism and chronic disease.
“CHIP-associated mutations in myeloid cells promote inflammatory signaling and accelerate atherosclerosis, establishing a causal link between somatic mosaicism and chronic disease”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [6]
The Abstract reports that TET2-deficient blood cells increased atherosclerotic plaque size in mice, while TET2-deficient macrophages increased NLRP3-mediated IL-1β secretion; it describes this as supporting a causal role in atherosclerosis. The claim generalizes that result from TET2 to CHIP-associated mutations broadly and does not retain the mouse-model qualification. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMost CHIP mouse models rely on BM transplantation following high-dose irradiation and inevitably increased inflammatory milieus.
“Currently, most CHIP mouse models rely on BM transplantation following high-dose irradiation and inevitably increased inflammatory milieus.16,24,39”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [24]
The passage labeled Abstract (page not provided) describes this CHIP mouse model using bone marrow transplantation into lethally irradiated recipients. It does not establish that most CHIP mouse models use this approach or that irradiation inevitably increases the inflammatory milieu; its inflammatory findings concern TET2 deficiency. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCHIP is known to be associated with atherosclerotic cardiovascular disease.
“CHIP is known to be associated with atherosclerotic cardiovascular disease11.”
From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [11]
The difference in plaque size between Tet2 knockout and control mice is only noted in the context of a high-fat diet; animals on a normal diet did not exhibit any measurable difference.
“The difference in the plaque size was only noted in the context of being fed a high-fat diet because animals on a normal diet did not exhibit any measurable difference [31]”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
Tet2 and Ppm1d mutant murine models demonstrate an increased inflammatory signature in mutant macrophages, with heightened inflammatory cytokine production upon pro-inflammatory stimulation in vitro.
“Tet2 and Ppm1d mutant murine models have demonstrated an increased inflammatory signature in mutant macrophages, with heightened inflammatory cytokine production upon pro-inflammatory stimulation in vitro [31,32,69,70].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
Mature myeloid cells, specifically macrophages, are responsible for the phenotype of larger atherosclerotic plaques in Tet2 knockout recipients.
“Both studies further tested and supported the hypothesis that mature myeloid cells, specifically macrophages, were responsible for this phenotype.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
Transplanted Tet2-deficient bone marrow cells have a competitive advantage over wild-type cells.
“It was shown that transplanted Tet2-deficient bone marrow cells had a competitive advantage over the wild-type cells.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [31]
TET2-mutant myeloid cells exhibit altered cytokine production, notably IL-1β, and inflammatory signaling, which has been directly linked to increased cardiovascular risk.
“TET2-mutant myeloid cells exhibit altered cytokine production (notably IL-1ß) and inflammatory signaling, which has been directly linked to increased cardiovascular risk [6,31].”
In the context of CHIP, Tet2 loss-of-function mutations in myeloid cells result in increased proinflammatory responses, with reported increases in both IL-1 and IL-6 production.
“in the context of CHIP, Tet2 loss-of-function mutations in myeloid cells result in increased proinflammatory responses, with reported increases in both IL-124,43 and IL-6 production,27”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [24]
People with clonal hematopoiesis are more prone to develop nonhematological disease, especially cardiovascular disease.
“That subjects with clonal hematopoiesis are more susceptible to develop nonhematological, most notably cardiovascular, disease”
From Aging of hematopoietic stem cells (2018) · cites this paper as [83]
D-2-hydroxyglutarate (D2HG) inhibits numerous demethylases, leading to changes in genomic and transcriptomic methylation profiles as well as gene expression and genome topology.
“D-2-hydroxyglutarate (D2HG) is one such oncometabolite, which inhibits numerous demethylases, leading to changes in genomic and transcriptomic methylation profiles as well as gene expression and genome topology 32,90-92 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [92]
Loss of Tet2 in bone marrow cells led to an increase in the size of atherosclerotic lesions in hyperlipidemic mice, an effect that could not be explained by quantitative changes in blood cell parameters of the mutant mice.
“Both groups found that loss of Tet2 in bone marrow cells led to an increase in the size of atherosclerotic lesions in hyperlipidemic mice, an effect that could not be explained by quantitative changes in blood cell parameters of the mutant mice 79,86.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [86]
Blockade of the pro-inflammatory cytokine IL-1B reversed the accelerated atherosclerosis seen in Tet2 mutant mice.
“In addition, blockade of the pro-inflammatory cytokine IL-1B reversed the accelerated atherosclerosis seen in Tet2 mutant mice 86.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [86]
Subsequent studies have confirmed over-expression of Il6 in Tet2-deficient macrophages challenged with low-density lipoprotein or endotoxin.
“Subsequent studies have confirmed the over-expression of Il6”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [86]
Il1b, IL8 family chemokines, and other inflammatory mediators show increased expression in Tet2-deficient macrophages challenged with low-density lipoprotein or endotoxin.
“also found that Il1b, IL8 family chemokines, and other inflammatory mediators show increased expression in Tet2-deficient macrophages challenged with low-density lipoprotein or endotoxin 79,86,92”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [86]
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“Both groups found that loss of Tet2 in bonemarrow cells led to an increase in the size of atherosclerotic lesions in hyperlipidemic mice, an effect that could not be explained by quantitative changes in blood cell parameters of the mutant mice (80, 87).”
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“Of these, data for TET2 have been particularly striking as atherosclerosis-prone mice transplanted with TET2-deficient bone marrow have accelerated atherosclerosis and premature heart failure, as well as excess production of IL-1β and IL-18.(107,108) Activation of the IL-1–associated NRLP3 inflammasome thus seems to b…”
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“ARCH contributes to several age-related pathologic conditions, including atherosclerosis (2), cardiovascular disease (3), vascular complications (4), and increased risk for developing hematologic malignancies (5, 6).”
Background<i>Tet2</i> deficiency–induced expansion of monocyte-derived macrophages promotes liver fibrosis
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“Emerging evidence highlights the anti-inflammatory role of 10–11 translocation 2 ( Tet2 ) in monocytes and macrophages (Fuster et al., 2017; Zhang et al., 2015; Cull et al., 2017; Lv et al., 2018).”
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Kopp, K., Silva, P., Damm, F., & Cosma, N. C. (2026) · Biomedicines · doi:10.3390/biomedicines14051012
- Authors
- Fuster, J. J., MacLauchlan, S., Zuriaga, M. A., Polackal, M. N., Ostriker, A. C., Chakraborty, R., Wu, C.-L., Sano, S., Muralidharan, S., Rius, C., Vuong, J., Jacob, S., Muralidhar, V., Robertson, A. A. B., Cooper, M. A., Andrés, V., Hirschi, K. K., Martin, K. A., & Walsh, K.
- Affiliations
- Boston University (US)
- Yale University (US)
- Spanish National Centre for Cardiovascular Research (ES)
- The University of Queensland (AU)
- Corresponding author
- Fuster, José J.
- Walsh, Kenneth
- ORCID
- Venue
- Science
- Published
- 2017-02-24
- Volume
- 355
- Issue
- 6327
- Pages
- 842-847
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5542057
- OpenAlex
- W2578808037
- Cited by
- 1,536
- References
- 30
- Citations by year
- 2026: 175 · 2025: 196 · 2024: 180 · 2023: 176 · 2022: 201 · 2021: 183 · 2020: 153 · 2019: 122 · 2018: 99 · 2017: 47 · 2012: 1
- FWCI
- 52.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (award297011, HL132564,HL126141,HL131006,HL119529 ,HL118430)
- American Heart Association (award297012, 17SDG33400213)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- clonal hematopoiesis, TET2 deficiency, atherosclerosis, bone marrow transplantation, macrophages, IL-1β, inflammasome, epigenetic regulators, cardiovascular disease, mouse model
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Macrophages, Mice, Inbred C57BL, Mutation, Proto-Oncogene Proteins, Receptors, LDL, Dioxygenases, Atherosclerosis, Mice, Plaque, Atherosclerotic, Inflammasomes
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