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Cited by 1,156Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationCancer Genomics and Diagnostics

Clonal hematopoiesis in human aging and disease

Open access
Jaiswal, Siddhartha, Ebert, Benjamin L.·2019·Science
DOI 10.1126/science.aan4673PMC PMC8050831
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Abstract

Cryptic signs of aging in our blood: Time is not a friend to our DNA. Aging is associated with an accumulation of somatic mutations in normal dividing cells, including the hematopoietic stem cells (HSCs) that give rise to all blood cells. Certain mutations in HSCs confer a fitness advantage that results in clonal expansions of mutant blood cells that sometimes—but not always—forecast the development of cancer and other age-related diseases. Jaiswal and Ebert review this process of “clonal hematopoiesis,” including the mechanisms by which it arises and the current state of knowledge regarding its effects on human health. Science , this issue p. eaan4673

AI snapshot

Written from the paper’s full text.

TL;DR

Clonal hematopoiesis, especially CHIP, is common with aging and driven largely by DNMT3A/TET2 mutations; it raises risk of blood cancers, cardiovascular disease, and mortality. Mouse and human data support causal roles in atherosclerosis and inflammation, though mechanisms and broader disease links remain uncertain.

Key findings

  • Clonal hematopoiesis is age-related: detectable in <1% of healthy individuals under age 40 but 10–20% of those age 70 or older; in one study, a median of ~18% of blood cells carried the mutations. Nearly two-thirds of clonal hematopoiesis was accounted for by loss-of-function mutations in DNMT3A and TET2, with ASXL1 third most common.
  • CHIP was associated with ~10-fold increased relative risk of hematological malignancies; 4% of CHIP carriers developed a blood cancer over 8 years, corresponding to ~0.5% conversion per year. Nested case-control studies found ~3- to 5-fold increased AML risk.
  • CHIP was associated with a 30–40% increased mortality risk and increased cardiovascular risk: coronary heart disease and ischemic stroke risk more than doubled, early-onset MI risk was four times higher, and JAK2 mutations conferred ~12-fold higher coronary heart disease risk and ~12-fold venous thrombosis risk.
  • Mouse models showed that Tet2 or Dnmt3a loss accelerates atherosclerosis and heart failure, with IL-1B blockade reversing accelerated atherosclerosis; CHIP genes also affect inflammatory pathways including IL6 and IL8.

Methods

  • Narrative review; no primary data collection or formal meta-analysis.
  • Synthesizes human population and exome sequencing studies, including cohorts of greater than 30,000 persons, nested case-control studies, and mouse models.
  • Main analysis is qualitative synthesis of genetic associations, clinical outcomes, and mechanistic experiments.

Limitations

  • Stated: mechanisms by which DNMT3A/TET2 and splicing factor mutations drive clonal expansion remain unclear; causality for non-malignant diseases beyond cardiovascular disease is not established, with type 2 diabetes possibly reflecting reverse causation and COPD potentially confounded by smoking.
  • Stated: prevalence estimates depend heavily on detection sensitivity, and the biological significance of smaller clones is unknown; clone trajectories vary between people and risk stratification remains incomplete.
  • Evident: as a narrative review, it lacks systematic search or quality assessment and provides no new primary data; risk estimates are drawn from heterogeneous studies.

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

Integrity signals

Registry

Crossref · 10.1126/science.aan4673

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 124 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Each HSC acquires approximately 1 exonic mutation per decade of life.

    “As each HSC acquires ~1 exonic mutation per decade of life 3,”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Welch JS The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264– 278, doi: 10.1016/j.cell.2012.06.023 (2012). 22817890 PMC3407563 source

      Not checked in the free run.

  • Premisecitation

    Studies of non-random X-chromosome inactivation in women led to the discovery that clonal hematopoiesis also occurs in individuals without cancer.

    “But in the 1990s, studies of non-random X-chromosome inactivation (XCI) in women led to the discovery that clonal hematopoiesis also occurs in individuals without cancer 18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Fey MF Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood 83, 931– 938 (1994). 8111064 source

      Not checked in the free run.

  • Premisereasoning

    Clonal hematopoiesis largely results from mutations in a very restricted set of genes.

    “The surprising result of this experiment of nature was that clonal hematopoiesis largely results from mutations in a very restricted set of genes.”
    Quote in the paperSubstantial claim
  • Premisereasoning

    Clonal hematopoiesis is highly prevalent in the elderly population.

    “This outgrowth, called “clonal hematopoiesis,” is highly prevalent in the elderly population.”
    • Also stated in: § Introduction · boosted
      “Indeed, numerous studies have now shown that such outgrowths of mutated blood cells, termed “clonal hematopoiesis,” are highly prevalent in the elderly.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Non-random X-chromosome inactivation in blood cells increases in frequency with age.

    “Importantly, non-random XCI in blood cells was observed to increase in frequency with age, although the underlying mechanism was unclear 19.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Champion KM, Gilbert JG, Asimakopoulos FA, Hinshelwood S & Green AR Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. British journal of haematology 97, 920– 926 (1997). 9217198 source

      Not checked in the free run.

  • May combine two claims. 31
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Premisecitation

    An equivalent state of somatic mutation-driven clonal expansions is pervasive in the epithelium of skin and esophagus, suggesting such expansions may be a characteristic of aging in several tissues.

    “An equivalent state is also pervasive in the epithelium of skin 14 and esophagus 15,16, suggesting that somatic mutation-driven clonal expansions may be a characteristic of aging in several tissues.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Martincorena I Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880– 886, doi: 10.1126/science.aaa6806 (2015). 25999502 PMC4471149 source

      Not checked in the free run.

    • cites [15] Martincorena I Somatic mutant clones colonize the human esophagus with age. Science 362, 911– 917, doi: 10.1126/science.aau3879 (2018). 30337457 PMC6298579 source

      Not checked in the free run.

    • cites [16] Yokoyama A Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312– 317, doi: 10.1038/s41586-018-0811-x (2019). 30602793 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    By age 70, an average person would be expected to harbor up to 1.4 million protein-coding variants, corresponding to an average of 70 mutations per gene, in at least one HSC.

    “by the age of 70 an average person would be expected to harbor up to 1.4 million protein-coding variants, corresponding to an average of 70 mutations per gene, in at least one HSC (Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DNA sequencing of HSCs from AML patients in remission revealed that stem cells with only a single driver mutation were often present, suggesting that pre-malignant clonal hematopoiesis was a generalizable finding in AML.

    “In later studies, DNA sequencing of HSCs from AML patients in remission revealed that stem cells with only a single driver mutation were often present, suggesting that pre-malignant clonal hematopoiesis was a generalizable finding in AML 23–25.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Jan M Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Science translational medicine 4, 149ra118, doi: 10.1126/scitranslmed.3004315 (2012). PMC4045621 22932223 source

      Not checked in the free run.

    • cites [24] Shlush LI Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328– 333, doi: 10.1038/nature13038 (2014). 24522528 PMC4991939 source

      Not checked in the free run.

    • cites [25] Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC & Majeti R Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A 111, 2548– 2553, doi: 10.1073/pnas.1324297111 (2014). 24550281 PMC3932921 source

      Not checked in the free run.

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

    Premisecitation

    Aging is associated with a steady increase in the number of somatic mutations in virtually all tissues.

    “Aging is associated with a steady increase in the number of somatic mutations in virtually all tissues 1–5.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [1] Blokzijl FJ, Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260 (2016). 27698416 PMC5536223 source

      Not checked in the free run.

    • cites [2] Hoang ML, Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing. Proc Natl Acad Sci U S A 113, 9846 (2016). 27528664 PMC5024639 source

      Not checked in the free run.

    • cites [3] Welch JS The origin and evolution of mutations in acute myeloid leukemia. Cell 150, 264– 278, doi: 10.1016/j.cell.2012.06.023 (2012). 22817890 PMC3407563 source

      Not checked in the free run.

    • cites [4] Martincorena I & Campbell PJ Somatic mutation in cancer and normal cells. Science 349, 1483– 1489, doi: 10.1126/science.aab4082 (2015). 26404825 source

      Not checked in the free run.

    • cites [5] Yizhak K, RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, doi: 10.1126/science.aaw0726 (2019). PMC7350423 31171663 source

      Not checked in the free run.

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

    Premisecitation

    Blood cancers such as chronic myeloid leukemia were first demonstrated to be clonal from karyotypic analysis and are the prototypical example of clonal hematopoiesis.

    “Blood cancers such as chronic myeloid leukemia were first demonstrated to be clonal from karyotypic analysis and are the prototypical example of clonal hematopoiesis 17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Rowley JD Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290– 293 (1973). 4126434 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Somatic clones were detectable in less than 1% of healthy individuals under age 40, but they increased in frequency with each decade of life.

    “Somatic clones were detectable in less than 1% of healthy individuals under age 40, but they increased in frequency with each decade of life.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

    “Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mouse models carrying loss-of-function mutations in either TET2 or DNMT3A show an HSC competitive advantage in vivo as well as a propensity for leukemia when cooperating mutations are present.

    “Mouse models carrying loss-of-function mutations in either of these genes clearly show an HSC competitive advantage in vivo as well as a propensity for leukemia when cooperating mutations are present 50–53.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [50] Ko M Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci U S A 108, 14566– 14571, doi: 10.1073/pnas.1112317108 (2011). 21873190 PMC3167529 source

      Not checked in the free run.

    • cites [51] Challen GA Dnmt3a is essential for hematopoietic stem cell differentiation. Nature genetics 44, 23– 31, doi: 10.1038/ng.1009 (2012). PMC3637952 22138693 source

      Not checked in the free run.

    • cites [52] Guryanova OA DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 22, 1488– 1495, doi: 10.1038/nm.4210 (2016). 27841873 PMC5359771 source

      Not checked in the free run.

    • cites [53] Cole CB Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. J Clin Invest 127, 3657– 3674, doi: 10.1172/JCI93041 (2017). 28872462 PMC5617681 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The accumulation of both small and large somatic variants is linked to aging, but the underlying biology of the two is generally non-overlapping.

    “While the accumulation of both small and large somatic variants are linked to aging, the underlying biology of the two is generally non-overlapping.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Large structural variation, such as gains or losses of large segments of chromosomes, increases with age and has clinically meaningful associations.

    “But large structural variation, such as gains or losses of large segments of chromosomes, also increases with age and has clinically meaningful associations 34–36.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Bonnefond A Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nature genetics 45, 1040– 1043, doi: 10.1038/ng.2700 (2013). 23852171 source

      Not checked in the free run.

    • cites [35] Jacobs KB Detectable clonal mosaicism and its relationship to aging and cancer. Nature genetics 44, 651– 658, doi: 10.1038/ng.2270 (2012). 22561519 PMC3372921 source

      Not checked in the free run.

    • cites [36] Loh PR Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 559, 350– 355, doi: 10.1038/s41586-018-0321-x (2018). 29995854 PMC6054542 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stem cells from mice with loss-of-function mutations in TET2 or DNMT3A are able to serially replate in colony forming assays over many generations, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells.

    “Stem cells from these mice are able to serially replate in colony forming assays over many generations, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells 54,55.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Moran-Crusio K Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer cell 20, 11– 24, doi: 10.1016/j.ccr.2011.06.001 (2011). 21723200 PMC3194039 source

      Not checked in the free run.

    • cites [55] Celik H Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation. Blood 125, 619– 628, doi: 10.1182/blood-2014-08-594564 (2015). 25416276 PMC4304107 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In one study, 4% of CHIP carriers developed a blood cancer over the subsequent 8 years, corresponding to approximately 0.5% of CHIP cases converting to malignancy per year.

    “In one study, 4% of CHIP carriers developed a blood cancer over the subsequent 8 years, corresponding to ~0.5% of CHIP cases converting to malignancy per year 28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previously described mutations in the blood of healthy persons such as BCR-ABL or BCL2 translocations were usually present in less than 0.01% of cells and were often transient.

    “For comparison, previously described mutations in the blood of healthy persons such as BCR-ABL or BCL2 translocations were usually present in less than 0.01% of cells and were often transient 29,30.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Biernaux C, Loos M, Sels A, Huez G & Stryckmans P Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 86, 3118– 3122 (1995). 7579406 source

      Not checked in the free run.

    • cites [30] Liu Y, Hernandez AM, Shibata D & Cortopassi GA BCL2 translocation frequency rises with age in humans. Proc Natl Acad Sci U S A 91, 8910– 8914 (1994). 8090743 PMC44716 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PIGA gene is required for the synthesis of glycophosphotidylinositol (GPI) and its loss results in down-regulation of several cell surface proteins that are GPI anchored.

    “The PIGA gene is required for the synthesis of glycophosphotidylinositol (GPI) and its loss results in down-regulation of several cell surface proteins that are GPI anchored 60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Brodsky RA Paroxysmal nocturnal hemoglobinuria. Blood 124, 2804– 2811, doi: 10.1182/blood-2014-02-522128 (2014). 25237200 PMC4215311 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Stochastic processes such as constriction of the stem cell pool with aging may lead to clonal hematopoiesis in the absence of a known driver mutation.

    “Stochastic processes such as constriction of the stem cell pool with aging may also lead to clonal hematopoiesis in the absence of a known driver mutation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CHIP itself does not denote a malignancy, nor is it associated with clinically significant alterations in blood counts.

    “CHIP itself does not denote a malignancy, nor is it associated with clinically significant alterations in blood counts 28,63.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

      Not checked in the free run.

    • cites [63] Buscarlet M DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753– 762, doi: 10.1182/blood-2017-04-777029 (2017). 28655780 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Loss of some GPI-anchored proteins may allow for immune escape, thus explaining selection for PIGA-mutated clones.

    “Loss of some of these proteins may allow for immune escape, thus explaining selection for PIGA-mutated clones.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CHIP has been reported to be more common in older men and smokers and less common in Hispanics, although these associations are all relatively modest.

    “For example, CHIP has been reported to be more common in older men 28 and smokers 27 and less common in Hispanics 28, although these associations are all relatively modest.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

      Not checked in the free run.

    • cites [27] Genovese G Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371, 2477– 2487, doi: 10.1056/NEJMoa1409405 (2014). 25426838 PMC4290021 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of Tet2 or Dnmt3a led to worsening heart function in a mouse model of congestive heart failure, corroborating the human genetic association.

    “Subsequent studies showed that loss of Tet2 or Dnmt3a led to worsening heart function in a mouse model of congestive heart failure, corroborating the human genetic association 87,88.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Sano S CRISPR-Mediated Gene Editing to Assess the Roles of Tet2 and Dnmt3a in Clonal Hematopoiesis and Cardiovascular Disease. Circ Res 123, 335– 341, doi: 10.1161/CIRCRESAHA.118.313225 (2018). 29728415 PMC6054544 source

      Not checked in the free run.

    • cites [88] Sano S Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1beta/NLRP3 Inflammasome. J Am Coll Cardiol 71, 875– 886, doi: 10.1016/j.jacc.2017.12.037 (2018). 29471939 PMC5828038 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CHIP in the setting of other cancers is likely to be especially pervasive and portends a poor prognosis.

    “These studies indicate that CHIP in the setting of other cancers is likely to be especially pervasive and portends a poor prognosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    JAK2 mutations prime neutrophils to form neutrophil extracellular traps, leading to thrombosis, which may also contribute to poor cardiovascular outcomes.

    “Furthermore, JAK2 mutations prime neutrophils to form neutrophil extracellular traps, leading to thrombosis, which may also contribute to poor cardiovascular outcomes 82.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Wolach O Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Science translational medicine 10, doi: 10.1126/scitranslmed.aan8292 (2018). PMC6442466 29643232 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Patients with CHIP also had increased mortality, most often due to progression of their primary malignancy.

    “Patients with CHIP also had increased mortality, most often due to progression of their primary malignancy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tissue architecture constrains the extent of clonal expansion within tissues such as gut or skin epithelium to patches that are rarely larger than a few square millimeters, but there is no such spatial restriction on HSCs, which freely admix throughout the bone marrow and body.

    “First, tissue architecture constrains the extent of clonal expansion within tissues such as gut or skin epithelium to patches that are rarely larger than a few square millimeters 15, but there is no such spatial restriction on HSCs, which freely admix throughout the bone marrow and body 78.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Martincorena I Somatic mutant clones colonize the human esophagus with age. Science 362, 911– 917, doi: 10.1126/science.aau3879 (2018). 30337457 PMC6298579 source

      Not checked in the free run.

    • cites [78] Wright DE, Wagers AJ, Gulati AP, Johnson FL & Weissman IL Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933– 1936, doi: 10.1126/science.1064081 (2001). 11729320 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Heart function in these studies was also improved with blockade of IL-1B, suggesting that this may be a common pathway for reversing the effects of CHIP in the heart.

    “Heart function in these studies was also improved with blockade of IL-1B, suggesting that this may be a common pathway for reversing the effects of CHIP in the heart.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The association between CHIP and T2D could represent reverse causation, as hyperglycemia might influence the development or expansion of clones by interfering with TET2 function.

    “this could represent a case of reverse causation, as hyperglycemia might influence the development or expansion of clones by interfering with TET2 function 90”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Wu D Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 559, 637– 641, doi: 10.1038/s41586-018-0350-5 (2018). 30022161 PMC6430198 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals with larger mutant clones had the greatest risk of cardiovascular disease, mirroring the situation for malignancy risk.

    “In addition, individuals with larger mutant clones had the greatest risk of cardiovascular disease, mirroring the situation for malignancy risk 79.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Jaiswal S Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377, 111– 121, doi: 10.1056/NEJMoa1701719 (2017). 28636844 PMC6717509 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Immune cells such as lymphocytes, granulocytes, and monocytes can migrate to and influence nearly every organ.

    “In contrast to tissue-specific cells or epithelia, immune cells such as lymphocytes, granulocytes, and monocytes can migrate to and influence nearly every organ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Myeloid malignancies were most common in individuals with CHIP, although some people with CHIP did develop lymphoid cancers.

    “Myeloid malignancies were most common, although some people with CHIP did develop lymphoid cancers 27,28.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Genovese G Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371, 2477– 2487, doi: 10.1056/NEJMoa1409405 (2014). 25426838 PMC4290021 source

      Not checked in the free run.

    • cites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Mutations in JAK2 have a well-described role in activating STAT transcription factors, which are central to immune response in several cell types involved in atherosclerosis.

    “Mutations in JAK2 have a well-described role in activating STAT transcription factors, which are central to immune response in several cell types involved in atherosclerosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Individuals with CHIP-associated JAK2 mutations were reported to have an approximately 12 times greater risk of developing venous thrombosis than those without CHIP, whereas individuals with mutations in other CHIP-associated genes had a doubling of the risk.

    “In a separate study (83), individuals with CHIP-associated JAK2 mutations were reported to have a ~12 times greater risk of developing venous thrombosis than those without CHIP, whereas individuals with mutations in other CHIP-associated genes had a doubling of the risk 82.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Wolach O Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Science translational medicine 10, doi: 10.1126/scitranslmed.aan8292 (2018). PMC6442466 29643232 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Jaiswal S Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377, 111– 121, doi: 10.1056/NEJMoa1701719 (2017). 28636844 PMC6717509 source

      Not checked in the free run.

    • cites [86] Fuster JJ Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science, doi: 10.1126/science.aag1381 (2017). PMC5542057 28104796 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The link between CHIP and COPD could be confounded by smoking, because CHIP was also strongly linked to smoking in these studies.

    “However, CHIP was also strongly linked to smoking in these studies, so the result could be confounded by this association.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Zink F Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742– 752, doi: 10.1182/blood-2017-02-769869 (2017). 28483762 PMC5553576 source

      Not checked in the free run.

    • cites [63] Buscarlet M DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753– 762, doi: 10.1182/blood-2017-04-777029 (2017). 28655780 source

      Not checked in the free run.

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

    Interpretationnone given

    Very little is known about why these specific gene expression changes are seen with loss of Dnmt3a.

    “Mechanistically, very little is known about why these specific gene expression changes are seen with loss of Dnmt3a.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth.

    “Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth 28,33.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Jaiswal S Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371, 2488– 2498, doi: 10.1056/NEJMoa1408617 (2014). 25426837 PMC4306669 source

      Not checked in the free run.

    • cites [33] Young AL, Challen GA, Birmann BM & Druley TE Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun 7, 12484, doi: 10.1038/ncomms12484 (2016). 27546487 PMC4996934 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Understanding the causes and consequences of clonal hematopoiesis may provide a framework to understand this process, and aging, more broadly.

    “Understanding the causes and consequences of clonal hematopoiesis may provide a framework to understand this process, and aging, more broadly.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    It is uncertain why some people have apparent clonal hematopoiesis in the absence of a known driver mutation.

    “It is also uncertain why some people have apparent clonal hematopoiesis in the absence of a known driver mutation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    CHIP is associated with blood cancers, cardiovascular disease, and overall mortality.

    “It is associated with blood cancers, cardiovascular disease, and overall mortality.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The two most commonly mutated genes in CHIP, DNMT3A and TET2, are opposing enzymes in DNA methylation, yet both lead to convergent phenotypes in stem cell biology and immunity.

    “It is striking that the two most commonly mutated genes in CHIP, DNMT3A and TET2, are opposing enzymes in DNA methylation, yet both lead to convergent phenotypes in stem cell biology and immunity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The mechanisms by which the CHIP-associated mutations cause clonal expansion and enhanced inflammation is a central unanswered question.

    “The mechanisms by which the CHIP-associated mutations cause clonal expansion and enhanced inflammation is also a central unanswered question.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bone marrow transplant recipients with hematological malignancies who received donor marrow from carriers of CHIP had higher rates of graft-versus-host disease and reduced relapse rates.

    “Bone marrow transplant recipients with hematological malignancies who received donor marrow from carriers of CHIP had higher rates of graft-versus-host disease and reduced relapse rates 95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Frick M Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol, JCO2018792184, doi: 10.1200/JCO.2018.79.2184 (2018). 30403573 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The process of mutation and clonal selection is likely to be universal across all organs and tissues.

    “The process of mutation and clonal selection is likely to be universal across all organs and tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The changes in expression are relatively modest for each gene (~2 to 3-fold increase) but appear to be biologically significant given the number of genes that are dysregulated and the breadth of phenotypes seen in Tet2 knockout mice.

    “The changes in expression are relatively modest for each gene (~2 to 3-fold increase) but appear to be biologically significant given the number of genes that are dysregulated and the breadth of phenotypes seen in Tet2 knockout mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    One possible explanation for the higher graft-versus-host disease and reduced relapse rates is that donor cells harboring the mutations were capable of mounting stronger immune responses against both normal host tissues and the tumor.

    “One possible explanation for this finding is that the donor cells harboring the mutations were capable of mounting stronger immune responses against both normal host tissues and the tumor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Frick M Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol, JCO2018792184, doi: 10.1200/JCO.2018.79.2184 (2018). 30403573 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The interaction of CHIP with other risk factors, such as having type 2 diabetes or elevated serum levels of C-reactive protein, may be synergistic for adverse outcomes.

    “Furthermore, the interaction of CHIP with other risk factors, such as having type 2 diabetes or elevated serum levels of C-reactive protein, may be synergistic for adverse outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    It is likely that cell extrinsic factors, like the microenvironment, the microbiome, or diet, will play a role.

    “It is likely that cell extrinsic factors, like the microenvironment, the microbiome, or diet, will play a role.”
    Quote in the paperNot a substantial claim
45 of 45

  • The authors state this as an assumption.

    Given a sufficiently large population, every possible mutation that can occur will occur in some HSCs.

    “These studies can be thought of as a natural experiment of saturation mutagenesis in humans, and can be summarized in a simple postulate—given a sufficiently large population, every possible mutation that can occur will occur in some HSCs.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • CHIP mutations increase the fitness of HSCs and myeloid progenitors.

    “as CHIP mutations are known to increase the fitness of HSCs and myeloid progenitors5”

    From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [5]

    The Introduction (page unavailable) describes mutations that confer a fitness advantage on HSCs, and “Mechanisms of clonal expansion” reports an HSC competitive advantage for some CHIP-associated mutations. The paper does not establish increased fitness in myeloid progenitors, and it notes that mice with certain CHIP-associated spliceosome mutations show an HSC competitive disadvantage. Thus the unqualified claim is broader than the evidence in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Most large-population-based studies define CHIP using a VAF threshold of ≥2%, reflecting the lower limit of reliable detection in standard whole-exome sequencing pipelines.

    “Most large-population-based studies define CHIP using a VAF threshold of ≥2%, reflecting the lower limit of reliable detection in standard whole-exome sequencing pipelines [2,32].”

    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 [32]

    The CHIP section states that the VAF threshold was set at 2%. It links that threshold to the likely clinical significance of clone size, not to a 2% lower limit of reliable whole-exome detection. The genome-sequencing section says whole-exome sequencing is relatively insensitive to smaller clones but gives no such detection limit; page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The prevalence of CHIP increases sharply with age, creating a significant biological intersection between individuals at risk for CHIP and late-onset AD.

    “The prevalence of CHIP increases sharply with age, creating a significant biological intersection between individuals at risk for CHIP and late-onset AD [9,32].”

    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 [32]

  • In humans, clonal haematopoiesis is a phenomenon where one or a few HSC clones disproportionately contribute to blood production over time.

    “In humans, this manifests itself as ‘clonal haematopoiesis’, where one or a few HSC clones disproportionately contribute to blood production over time48,49.”

    From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [49]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Venous-thrombosis study is cited as reference 83

    Minor

    The text identifies reference 83 as a study of venous thrombosis in people with CHIP, but the paper's own reference 83 concerns red blood cell distribution width and risk of death.

1 of 1

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Related

Authors
Jaiswal, S., & Ebert, B. L.
Affiliations
  • Stanford Medicine (US)
  • Broad Institute (US)
Corresponding author
  • Jaiswal, Siddhartha
  • Ebert, Benjamin L.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2019-11
Volume
366
Issue
6465
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aan4673
PMC
PMC8050831
OpenAlex
W2982291252
Semantic Scholar
6d1a7a80dacac969118008d44a082733bff68245
Cited by
1,156
References
98
Citations by year
2026: 173 · 2025: 222 · 2024: 206 · 2023: 169 · 2022: 164 · 2021: 136 · 2020: 83 · 2019: 3
FWCI
15.36
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Japanese Society of Hematology
Funders
  • National Institutes of Health (P01CA066996, P50CA206963, R01HL082945)
  • Burroughs Wellcome Fund
  • Edward P. Evans Foundation
  • Ludwig Institute for Cancer Research
  • Fondation Leducq
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
clonal hematopoiesis, somatic mutations, aging, hematopoietic stem cells, cancer risk, immune function
MeSH terms
Aged, Aging, Animals, Cardiovascular Diseases, Clone Cells, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mutation, Precancerous Conditions, Hematologic Neoplasms, Clonal Evolution

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 2026-10-10.

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

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.

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