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Cited by 79Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationBlood disorders and treatments

Clonal hematopoiesis and inflammation – the perpetual cycle

Open access
Avagyan, Serine, Zon, Leonard I.·2023·Trends in Cell Biology
DOI 10.1016/j.tcb.2022.12.001PMC PMC10310890
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Abstract

Acquired genetic or cytogenetic alterations in a blood stem cell that confer clonal fitness promote its relative expansion leading to clonal hematopoiesis (CH). Despite a largely intact hematopoietic output, CH is associated with a heightened risk of progression to hematologic malignancies and with non-hematologic health manifestations, including cardiovascular disease and overall mortality. We focus on the evidence for the role of inflammation in establishing, maintaining and reciprocally being affected by CH. We describe the known pro-inflammatory signals associated with CH and preclinical studies that elucidated the cellular mechanisms involved. We review the evolving literature on early-onset CH in germline predisposition conditions and the possible role of immune dysregulation in this context.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that clonal hematopoiesis (CH) and inflammation form a perpetual cycle: acquired mutations in hematopoietic stem/progenitor cells (HSPCs) can drive pro-inflammatory myeloid progeny and systemic disease, while inflammatory signals select for and maintain mutant clones. It synthesizes preclinical models and human cohort data on CH mechanisms, germline predisposition, and anti-inflammatory therapeutic strategies.

Key findings

  • CH prevalence depends on assay: whole-exome/genome sequencing identifies clonal growth without driver mutations up to 50% by the ninth decade, targeted panels report 30–90% by age 90, and error-corrected sequencing detects clones as small as 0.03%. The top recurrent leukemia-associated CH genes remain DNMT3A, TET2, and ASXL1.
  • Preclinical models show mutant clones can worsen inflammatory disease: Tet2-deficient marrow had a competitive advantage, and Ldlr−/− recipients on a high-fat diet developed larger atherosclerotic plaques with increased Il-1β and Il-6; the plaque difference was seen only on high-fat diet. In a Jak2-mutant heart failure model, recipients had larger infarct size, increased cardiac hypertrophy, and fibrosis, with elevated Il-6, Il-1β, and TNF-α.
  • Inflammation can select for mutant HSPCs: Dnmt3a-mutant cells showed advantage only with chronic Mycobacterium avium infection; Ifngr−/−;Dnmt3a−/− cells lost competitive ability, and IFN-γ injections promoted Dnmt3a-mutant growth. Human studies associate CH with elevated IL-8, IL-1β, IL-6, IL-18, IFN-γ, and C-reactive protein; HIV-positive adults had increased CH with DNMT3A, TET2, and ASXL1 variants.
  • Therapeutic proof-of-principle includes CANTOS exploratory analysis, where anti-IL-1β canakinumab modestly decreased cardiovascular events in TET2 CH (hazard ratio 0.38, 95% CI 0.15–0.96) but not non-TET2 CH; in mice, NF-κB/STAT3 inhibitor E3330 or SHP2 inhibitor SHP099 abrogated competitive growth of aged Tet2−/− cells and reduced serum IL-6.

Methods

  • Narrative review, not a primary study; it synthesizes preclinical animal models (mouse and zebrafish) and human cohort/sequencing studies.
  • Covers CH definitions, mutational landscape, inflammation mechanisms, innate/adaptive immunity, survival pathways in mutant HSPCs, germline predisposition, and candidate therapies.
  • No systematic search strategy, meta-analysis, or primary data collection is described.

Limitations

  • The authors state that murine CH models rely heavily on transplantation assays, which can introduce clonal bottlenecks, select for other fitness characteristics, force replicative stressors, and study competition in an irradiated niche; data on endogenous mutant HSPC compartments are limited.
  • The authors note that single-cell multi-omic assays currently have low recovery rates for accurately mapping mutant versus wild-type cells and are limited to small-scale investigations, constraining generalizable conclusions.
  • The text makes evident that several mechanistic links are hypotheses or speculative (e.g., trained innate immunity, mutation-dependent anti-inflammatory pathways in HSPCs), human CH–cytokine associations are correlative, and whether inflammation causes CH or CH causes inflammation remains an open question.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tcb.2022.12.001

Cites

120 of 120 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

66 of 77 cited sources checked · 27 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Deletion of Nr4a1 and Nr4a3 results in loss of self-renewal of hematopoietic stem and progenitor cells.

    “Deletion of Nr4a1 and Nr4a3 resulted in loss of self-renewal of HSPCs [85,86].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [85] Land RH (2015) The orphan nuclear receptor NR4A1 specifies a distinct subpopulation of quiescent myeloid-biased long-term HSCs. Stem Cells 33, 278– 288 25284014 PMC4270858 source

      The Introduction (page unavailable) reports that mice deficient in both NR4A1 and NR4A3 develop acute myeloid leukemia, while mice with reduced NR4A gene dosage show increased HSPC proliferation. It does not report that deletion of both genes causes loss of HSPC self-renewal; the Discussion links NR4A1 to quiescence and reconstitution potential but does not establish that outcome. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [86] Freire PR and Conneely OM (2018) NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling. Blood 131, 1081 29343483 PMC5863701 source

      The section titled “Nr4a1/3-null HSCs retain stem cell capacity” (page not provided) reports similar colony-forming capacity and long-term engraftment in knockout and control HSCs. The Discussion explicitly says that Nr4a1/3-null HSCs retain self-renewal capabilities, contrary to the claimed loss. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    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].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [31] Fuster JJ (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842– 847 28104796 PMC5542057 source
    • cites [32] Jaiswal S (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111– 121 28636844 PMC6717509 source

      The Results section (page not provided) reports an increased inflammatory gene signature in Tet2−/− mouse macrophages and greater cytokine and chemokine secretion after LDL loading or endotoxin exposure in vitro. The cited paper does not report a Ppm1d mutant murine model or the corresponding macrophage finding for Ppm1d. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [69] Abegunde SO (2018) An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59, 60– 65 29195897 source
    • cites [70] Yura Y (2021) The cancer therapy-related clonal hematopoiesis driver gene ppm1d promotes inflammation and nonischemic heart failure in mice. Circ. Res. 129, 684– 698 34315245 PMC8409899 source
  • Premisecitation

    Gene-specific fitness is independent of when the mutation was acquired.

    “Corroborative studies using longitudinal data have shown that gene-specific fitness is independent of when the mutation was acquired [44].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Robertson NA (2022) Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects. Nat. Med. 28, 1439– 1446 35788175 PMC9307482 source
  • Premisecitation

    CH is associated with chronic obstructive pulmonary disease and other pulmonary disease.

    “Various other systemic effects have been described in association with CH, including chronic obstructive pulmonary disease and other pulmonary disease [16,33,34]”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [16] Zink F (2017) Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742– 752 28483762 PMC5553576 source

      In “Association of CH with other phenotypes” (page not provided), the paper reports a significant association between CH, measured by WGS-outlier status, and chronic pulmonary disease. It does not report a separate association with chronic obstructive pulmonary disease (COPD); COPD appears elsewhere as a variable used for adjustment. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [33] Buscarlet M (2017) DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753– 762 28655780 source

      In “Risk factors for acquiring mutations,” the paper reports a significant association between TET2 mutations and a self-reported COPD-asthma category. It does not establish separate associations for COPD and other pulmonary diseases, or for clonal hematopoiesis regardless of mutation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [34] Miller PG (2022) Association of clonal hematopoiesis with chronic obstructive pulmonary disease. Blood 139, 357– 368 34855941 PMC8777202 source
  • Premisecitation

    Tet2 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].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Fuster JJ (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842– 847 28104796 PMC5542057 source

      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
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Premisecitation

    DNMT3A mutant clones are relatively slow-growing at ~5% per year while SRSF2 mutant clones may grow as fast as 20% per year.

    “for example, DNMT3A mutant clones are relatively slow-growing at ~5% per year while SRSF2 mutants clones may grow as fast as 20% per year [21].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Fabre MA (2022) The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606, 335– 342 35650444 PMC9177423 source

  • May combine two claims.

    Premisecitation

    Ldlr−/− 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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Fuster JJ (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842– 847 28104796 PMC5542057 source

      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 measured

  • May combine two claims.

    Premisecitation

    Human MDS HSPCs show significant innate immune system dysregulation and resistance to the pro-proliferative effects of inflammation.

    “Human myelodysplastic syndrome (MDS) HSPCs have shown significant innate immune system dysregulation and resistance to the pro-proliferative effects of inflammation [69,80,81].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [69] Abegunde SO (2018) An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59, 60– 65 29195897 source
    • cites [80] Barreyro L (2018) Chronic immune response dysregulation in MDS pathogenesis. Blood 132, 1553– 1560 30104218 PMC6182269 source

      The section “Expression of immune-related genes in MDS hematopoietic stem/progenitor cells” says innate immune-related gene dysregulation is common in MDS HSPCs. The cited paper does not establish that MDS HSPCs resist inflammation’s pro-proliferative effects; its “Activation of immune receptors in MDS” section instead describes increased proliferation after TLR stimulation in human HSPCs generally, without specifying MDS HSPCs. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [81] Trowbridge JJ and Starczynowski DT (2021) Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS. J. Exp. Med. 218, e20201544 34129017 PMC8210621 source

      The MDS section states that innate immune and inflammatory signaling is dysregulated in human MDS HSPCs. The Preleukemia and MDS section describes a different response to inflammation and a competitive advantage over normal HSPCs, but does not establish resistance to inflammation’s pro-proliferative effects; it suggests that inflammatory conditions may favor MDS HSPC expansion. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Repetitive sterile inflammation results in hypomethylation of promoters of inflammatory response genes, leading to the conclusion that self-renewal is epigenetically regulated in this model.

    “while repetitive sterile inflammation did not result in major gene expression changes, it resulted in hypomethylation of promoters of inflammatory (particularly interferon) response genes, leading them to conclude that self-renewal is epigenetically regulated in this model.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [65] Bogeska R (2022) Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging. Cell Stem Cell 29, 1273– 1284 35858618 PMC9357150 source

      The Results section reports no profound sustained gene-expression changes in most LT-HSCs and identifies hypomethylation of promoters of interferon/inflammatory-response genes after inflammatory challenge. It says this demonstrates a lack of self-renewal at the epigenetic level, but does not establish that methylation changes regulate self-renewal; that causal conclusion goes beyond the passage. Page numbers are not available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Ppm1d loss confers an advantage only in the context of the selective environment of cytotoxic chemotherapy or radiation, but not in steady-state post-transplant conditions.

    “Ppm1d loss confers an advantage only in the context of the selective environment of cytotoxic chemotherapy or radiation, but not in steady-state post-transplant conditions [53,54].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [53] Kahn JD (2018) PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132, 1095– 1105 29954749 PMC6137556 source
    • cites [54] Hsu JI (2018) PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell 23, 700– 713 30388424 PMC6224657 source

      The Results sections on cisplatin exposure and transplantation report that Ppm1d R451X mutant cells gained an advantage with cisplatin but did not expand after transplantation without chemotherapy (page unavailable in our copy). The claim substitutes Ppm1d loss for that mutation: the paper explicitly distinguishes loss in knockout mice from hyperactivity in the mutations it studied. It also does not establish a selective advantage under radiation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Fuster JJ (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842– 847 28104796 PMC5542057 source

  • May combine two claims.

    Premisecitation

    CH 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].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [31] Fuster JJ (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842– 847 28104796 PMC5542057 source

      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 measured
    • cites [32] Jaiswal S (2017) Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111– 121 28636844 PMC6717509 source

  • May combine two claims.

    Premisecitation

    In a Jak2 mutation model of coronary artery ligation and heart failure, recipients of mutant myeloid cells show larger infarct size, increased cardiac hypertrophy, and eventually increased fibrosis.

    “the authors showed in recipients of the mutant myeloid cells that there was larger infarct size, increased cardiac hypertrophy, and eventually increased fibrosis [38].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Sano S (2019) JAK2 V617F-mediated clonal hematopoiesis accelerates pathological remodeling in murine heart failure. JACC Basic Transl. Sci. 4, 684– 697 31709318 PMC6834960 source

      The Results section on experimental MI reports enlarged infarct areas and increased fibrosis after LAD ligation in recipients of myeloid-specific JAK2V617F cells (Figure 3E). It reports increased cardiac hypertrophy in a separate pressure-overload model (Figure 4), not in the LAD-ligation model, so the claim conflates the two experiments. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IFN-γ signaling is necessary and sufficient for the fitness of Dnmt3a knockout hematopoiesis.

    “supporting that IFN-γ signaling is necessary and sufficient for the fitness of Dnmt3a knockout hematopoiesis.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [49] Hormaechea-Agulla D (2021) Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 28, 1428– 1442 33743191 PMC8349829 source
    • cites [61] Matatall KA (2016) Chronic infection depletes hematopoietic stem cells through stress-induced terminal differentiation. Cell Rep. 17, 2584– 2595 27926863 PMC5161248 source

      The Results sections on IFNγ-dependent HSC engraftment and BATF2 loss of function examine infection-related HSC impairment and BATF2-knockout progenitors, respectively; no page numbers are available in our copy. A search for Dnmt3a-knockout hematopoiesis and IFNγ-related fitness found no passage addressing whether IFNγ signaling is necessary and sufficient for that fitness. (LLM, conf=0.70)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Murine Dnmt3a mutant hematopoiesis promotes osteoporosis and bone loss through increased osteoclastogenesis that can be reversed by bisphosphonate treatment.

    “murine Dnmt3a mutant hematopoiesis has been shown promote osteoporosis and bone loss through increased osteoclastogenesis that could be reversed by bisphosphonate treatment [40].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Kim PG (2021) Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. J. Exp. Med. 218, e20211872 34698806 PMC8552148 source

  • May combine two claims.

    Premisecitation

    Positive correlations are observed between IL-6 levels and DNMT3A, TET2, and ASXL1 mutant CH, and heightened IL-18 levels with JAK2 and SF3B1.

    “positive correlations were observed between IL-6 levels and DNMT3A, TET2, and ASXL1 mutant CH, heightened IL-18 levels with JAK2 and SF3B1 [20]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Bick AG (2020) Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586, 763– 768 33057201 PMC7944936 source

      The CHIP phenotypic associations section (page not specified) reports increased IL-6 for CHIP carriers in aggregate and increased IL-18 for JAK2 and SF3B1 CHIP. It does not report separate positive IL-6 associations for DNMT3A, TET2, and ASXL1 CHIP; its gene-specific finding for TET2 concerns IL-1β. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TII occurs not only in mature myeloid cells but also in immature progenitors, and thus can be long-lived.

    “Studies have shown that TII occurs not only in mature myeloid cells, as previously believed, but also in immature progenitors, and thus can be long-lived [74,76].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [74] Kaufmann E (2018) BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176– 190 29328912 source
    • cites [76] Mitroulis I (2018) Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147– 161 29328910 PMC5766828 source

  • May combine two claims.

    Premisecitation

    In competitive transplantation into recipient wild-type mice without additional stimuli, the advantage of Dnmt3a mutant cells is not significant and is only apparent in the context of chronic Mycobacterium avium infection.

    “However, in competitive transplantation into recipient wild-type mice without additional stimuli, the advantage of Dnmt3a mutant cells is not significant and is only apparent in the context of chronic Mycobacterium avium (M. avium) infection [49].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [49] Hormaechea-Agulla D (2021) Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 28, 1428– 1442 33743191 PMC8349829 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In intestinal stem cells, Apc mutant clones secrete WNT antagonists that promote the differentiation of wild-type clones.

    “A similar positive feedforward model of competitive outgrowth of mutant cells has been shown in intestinal stem cells where Apc mutant clones secrete WNT antagonists that promote the differentiation of wild-type clones [87];”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [87] van Neerven SM (2021) Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature 594, 436– 441 34079128 source

      The retrieved passages labeled Abstract contain bibliographic metadata and the paper title, but no findings about WNT antagonists or wild-type cell differentiation. Searches for the claim’s wording and for NOTUM yielded no relevant passage in our copy, so the proposed mechanism cannot be verified from it. (LLM, conf=0.70)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Because Apc-mutant cells themselves are insensitive to WNT modulation, this leads to their expansion and adenoma formation.

    “because Apc-mutant cells themselves are insensitive to WNT modulation, this leads to their expansion and adenoma formation.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [87] van Neerven SM (2021) Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature 594, 436– 441 34079128 source

      The indexed passages contain bibliographic metadata and the title (unlabelled and Abstract-labelled entries, no page given), but no passage about WNT modulation or the proposed cause of Apc-mutant cell expansion and adenoma formation. Searches for WNT insensitivity and for expansion and adenoma formation returned no relevant text from the paper. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NR4A1 and other NR4A family members have an immunomodulatory role in mature cell types, most commonly in T cells and macrophages.

    “NR4A1 and other NR4A family members are known for their immunomodulatory role in mature cell types, most commonly in T cell and macrophages [83,84].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [83] Boulet S (2022) Role of NR4A family members in myeloid cells and leukemia. Curr. Res. Immunol. 3, 23– 36 35496823 PMC9040138 source

      The section ‘NR4As limit the inflammatory macrophage response’ describes how NR4A family members regulate macrophage inflammation, and the macrophage section mentions NR4A1’s role in regulatory T-cell development. The paper does not establish that T cells and macrophages are the cell types in which these roles occur most commonly; its discussion also covers other myeloid cells. Page numbers were not available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [84] Odagiu L (2021) Role of the orphan nuclear receptor NR4A family in T-cell biology. Front. Endocrinol. 11, 1107 PMC7883379 33597928 source

      The “NR4As and Peripheral CD4+ T Cell Responses” section describes immunomodulatory functions of NR4A1 and other NR4A members in mature T cells, including maintenance of Treg identity. The paper mentions macrophages as cells helped by CD4+ T cells, but does not establish an NR4A role in macrophages or the claim that T cells and macrophages are the most common cell types for that role. Page numbers were not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisenone given

    CH is associated with a heightened risk of progression to hematologic malignancies and with non-hematologic health manifestations, including cardiovascular disease and overall mortality.

    “Despite a largely intact hematopoietic output, CH is associated with a heightened risk of progression to hematologic malignancies and with non-hematologic health manifestations, including cardiovascular disease and overall mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    CH mutations may lead to a relative increase in proliferative rate or an increased proliferative response to external stimuli, including systemic disease such as atherosclerosis.

    “The CH mutations may lead to a relative increase in proliferative rate or an increased proliferative response to external stimuli, including systemic disease such as atherosclerosis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from murine transplantation models are informative about endogenous human CH.

  • May combine two claims.

    Interpretationreasoning

    CH mutations occur in HSPCs, and thus also result in mutant lymphoid cells, including T cells, which are capable of altering the immune microenvironment.

    “The CH mutations occur in HSPCs, and thus also result in mutant lymphoid cells, including T cells, which are also capable of altering the immune microenvironment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The rate for a given mutant clone is generally constant, and could potentially be altered by environmental changes or the acquisition of additional mutations that may lead to clonal bursts.

    “These early data suggest that the rate for a given mutant clone is generally constant, and could potentially be altered by environmental changes or the acquisition of additional mutations that may lead to clonal bursts.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from murine transplantation models are informative about endogenous human CH.

  • May combine two claims.

    Premisecitation

    In mutant zebrafish hematopoietic stem and progenitor cells, overexpression of socs3a, atf3, and nr4a1 was found, and these molecules were critical for regulating intracellular inflammatory responses.

    “When comparing the transcriptional profile of HSPCs in mutant zebrafish to control animals, the authors found overexpression of several molecules, such as socs3a, atf3, and nr4a1, that were critical for regulating the intracellular inflammatory responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Avagyan S (2021) Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science 374, 768– 772 34735227 source

  • May combine two claims.

    Premisecitation

    In vitro studies using murine Tet2−/− lineage marker-negative marrow cells with 24 days of TNF-α exposure show decreased apoptosis, suggesting that immature cells may better survive prolonged inflammatory stimuli.

    “In vitro studies using murine Tet2−/− lineage marker-negative marrow cells with 24 days of TNF-α exposure showed decreased apoptosis [69], suggesting that the immature cells may better survive prolonged inflammatory stimuli.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Abegunde SO (2018) An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59, 60– 65 29195897 source
22 of 22

  • The authors state this as an assumption.

    Somatic mutations are acquired stochastically in a cell in a given tissue.

    “Assuming stochastic acquisition of mutations in a cell in a given tissue, it remains unclear what prompts the advantage of a clone with a somatic mutation over others.”

  • The paper relies on this without support.

    Findings from murine transplantation models are informative about endogenous human CH.

    “Furthermore, murine models to date have relied on transplantation assays for assessing the functional consequences of CH mutations. The transplantation model, although informative, can present clonal bottlenecks, selection for other fitness characteristics, force replicative stressors otherwise not experienced by HSPC clones, and describe cellular competition in an irradiated niche.”

  • The paper relies on this without support.

    The role of NR4A family members in hematopoietic stem and progenitor cells with respect to inflammatory pathway regulation is not known.

    “The role of NR4A family members in HSPCs with respect to inflammatory pathway regulation is not known.”

  • The paper relies on this without support.

    How mutant ASXL1 induces NR4A1 expression is not known.

    “How mutant ASXL1 induces NR4A1 expression is not known.”
4 of 4

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Authors
Avagyan, S., & Zon, L. I.
Affiliations
Boston Children's Hospital (US)
Corresponding author
Avagyan, Serine
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2023-08
Volume
33
Issue
8
Pages
695-707
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2022.12.001
PMC
PMC10310890
OpenAlex
W4313397527
Cited by
79
References
120
Citations by year
2026: 23 · 2025: 31 · 2024: 19 · 2023: 6
FWCI
2.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Alex's Lemonade Stand Foundation for Childhood Cancer
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
clonal hematopoiesis, inflammation, hematologic malignancy risk, cardiovascular disease, clonal fitness, germline predisposition, immune dysregulation, hematopoietic stem cells, clonal expansion
MeSH terms
Clonal Hematopoiesis, Hematopoiesis, Humans, Inflammation, Mutation, Risk Factors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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