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Clonal hematopoiesis in human aging and disease
Open accessAbstract
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
Overview
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.
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Claims the paper makes
80 Not checked yet · 26 Own interpretation · 20 No basis given · 5 Own result
In the paper
“As each HSC acquires ~1 exonic mutation per decade of life 3,”
§ Clonal hematopoiesis in human aging and disease > Introduction
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > A brief history of clonal hematopoiesis
What the sources say
- Not checked yetcites [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
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In the paper
“The surprising result of this experiment of nature was that clonal hematopoiesis largely results from mutations in a very restricted set of genes.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Abstract
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In the paper
“Importantly, non-random XCI in blood cells was observed to increase in frequency with age, although the underlying mechanism was unclear 19.”
§ Clonal hematopoiesis in human aging and disease > A brief history of clonal hematopoiesis
What the sources say
- Not checked yetcites [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
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In the paper
“The third most commonly mutated gene was ASXL1, a chromatin regulator, while mutations in splicing factors (SF3B1, SRSF2, PRPF8, U2AF1) were also frequent.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
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In the paper
“This was the first demonstration that mutation-driven clonal hematopoiesis occurs in healthy persons 20.”
§ Clonal hematopoiesis in human aging and disease > A brief history of clonal hematopoiesis
What the sources say
- Not checked yetcites [20] Busque L Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nature genetics 44, 1179– 1181, doi: 10.1038/ng.2413 (2012). 23001125 PMC3483435 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Like most cancers, AML generally results from several driver mutations that occur sequentially in the same clone over time 3.”
§ Clonal hematopoiesis in human aging and disease > A brief history of clonal hematopoiesis
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mutations in classical oncogenes and tumor suppressors, such as those involved in cellular growth signaling (JAK2, GNAS, GNB1, CBL) and the DNA damage response (TP53, PPM1D), were seen but were not the most common.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
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In the paper
“The size of these mutant clones was massive; in one study, a median of ~18% of blood cells carried the mutations 28.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 31
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Clonal hematopoiesis in human aging and disease > Introduction
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > A brief history of clonal hematopoiesis
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Aging is associated with a steady increase in the number of somatic mutations in virtually all tissues 1–5.”
§ Clonal hematopoiesis in human aging and disease > Introduction
What the sources say
- Not checked yetcites [1] Blokzijl FJ, Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260 (2016). 27698416 PMC5536223 source
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > A brief history of clonal hematopoiesis
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Somatic clones were detectable in less than 1% of healthy individuals under age 40, but they increased in frequency with each decade of life.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.”
§ Clonal hematopoiesis in human aging and disease > Abstract
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Mechanisms of clonal expansion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“While the accumulation of both small and large somatic variants are linked to aging, the underlying biology of the two is generally non-overlapping.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Mechanisms of clonal expansion
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and hematological malignancy
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis in the genome sequencing era
What the sources say
- Not checked yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Mechanisms of clonal expansion
What the sources say
- Not checked yetcites [60] Brodsky RA Paroxysmal nocturnal hemoglobinuria. Blood 124, 2804– 2811, doi: 10.1182/blood-2014-02-522128 (2014). 25237200 PMC4215311 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Clonal hematopoiesis of indeterminate potential (CHIP)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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In the paper
“CHIP itself does not denote a malignancy, nor is it associated with clinically significant alterations in blood counts 28,63.”
§ Clonal hematopoiesis in human aging and disease > CHIP and hematological malignancy
What the sources say
- Not checked yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loss of some of these proteins may allow for immune escape, thus explaining selection for PIGA-mutated clones.”
§ Clonal hematopoiesis in human aging and disease > Mechanisms of clonal expansion
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Mechanisms of clonal expansion
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies indicate that CHIP in the setting of other cancers is likely to be especially pervasive and portends a poor prognosis.”
§ Clonal hematopoiesis in human aging and disease > CHIP and hematological malignancy
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Furthermore, JAK2 mutations prime neutrophils to form neutrophil extracellular traps, leading to thrombosis, which may also contribute to poor cardiovascular outcomes 82.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Patients with CHIP also had increased mortality, most often due to progression of their primary malignancy.”
§ Clonal hematopoiesis in human aging and disease > CHIP and hematological malignancy
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“this could represent a case of reverse causation, as hyperglycemia might influence the development or expansion of clones by interfering with TET2 function 90”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In addition, individuals with larger mutant clones had the greatest risk of cardiovascular disease, mirroring the situation for malignancy risk 79.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In contrast to tissue-specific cells or epithelia, immune cells such as lymphocytes, granulocytes, and monocytes can migrate to and influence nearly every organ.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Myeloid malignancies were most common, although some people with CHIP did develop lymphoid cancers 27,28.”
§ Clonal hematopoiesis in human aging and disease > CHIP and hematological malignancy
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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 yetcites [86] Fuster JJ Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science, doi: 10.1126/science.aag1381 (2017). PMC5542057 28104796 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, CHIP was also strongly linked to smoking in these studies, so the result could be confounded by this association.”
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mechanistically, very little is known about why these specific gene expression changes are seen with loss of Dnmt3a.”
§ Clonal hematopoiesis in human aging and disease > Immune function and CHIP
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth 28,33.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
What the sources say
- Not checked yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Understanding the causes and consequences of clonal hematopoiesis may provide a framework to understand this process, and aging, more broadly.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is also uncertain why some people have apparent clonal hematopoiesis in the absence of a known driver mutation.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“It is associated with blood cancers, cardiovascular disease, and overall mortality.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mechanisms by which the CHIP-associated mutations cause clonal expansion and enhanced inflammation is also a central unanswered question.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Immune function and CHIP
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The process of mutation and clonal selection is likely to be universal across all organs and tissues.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Immune function and CHIP
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Immune function and CHIP
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is likely that cell extrinsic factors, like the microenvironment, the microbiome, or diet, will play a role.”
§ Clonal hematopoiesis in human aging and disease > Future outlook
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“Examples include the possible links between clonal haematopoiesis and cardiovascular disease54; between mutations in liver disease and insulin resistance55; and between driver mutations in cavernomas and brain haemorrhages49,53,56.”
From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [56]
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Clonal hematopoiesis in human aging and disease > CHIP and non-malignant disease
“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”
§ Clonal hematopoiesis in human aging and disease > References
“83. Patel KV, Ferrucci L, Ershler WB, Longo DL & Guralnik JM Red blood cell distribution width and the risk of death in middle-aged and older adults.”
Citations
Cites
Stem cells, cancer, and cancer stem cells
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001) · Nature · doi:10.1038/35102167 · Cited by 9,738 · cited 1×
“If the first mutation to be acquired leads to clonal expansion without malignant transformation, it should be possible to identify a premalignant stage in which only the initiating lesion is present (22).”
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The Cancer Genome Atlas Research Network (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1301689 · Cited by 5,078 · cited 16×
“M. A. Sanders et al., MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.”
BackgroundInfluentialAge-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841 · cited 9×
“Indeed, some individuals with clonal hematopoiesis have nearly all of their blood cells arising from a single mutated HSC (29).”
BackgroundInfluentialSelf-citationROWLEY, J. D. (1973) · Nature · doi:10.1038/243290a0 · Cited by 4,291 · cited 1×
“Blood cancers such as chronic myeloid leukemia were first demonstrated to be clonal from karyotypic analysis and are the prototypical example of clonal hematopoiesis (18).”
BackgroundChronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases
Franceschi, C., & Campisi, J. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glu057 · Cited by 3,891 · cited 1×
“Growing evidence thus supports a role for the commonlymutatedCHIP genes in immune function, and CHIP may underlie some part of the phenomenon termed “inflammaging,” the age-associated increase in systemic inflammation (98).”
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Kralovics, R., Passamonti, F., Buser, A. S., Teo, S.-S., Tiedt, R., Passweg, J. R., Tichelli, A., Cazzola, M., & Skoda, R. C. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa051113 · Cited by 3,470 · cited 1×
“Activating mutations in JAK2 allow constitutive signaling though growth factor receptors, thus leading to clonal expansion by enhanced proliferation of cells that carry this mutation (46).”
BackgroundTet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451 · cited 1×
“TET2 is one of three enzymes responsible for catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and further intermediates, which can eventually lead to demethylation (49, 50).”
DNA methylation-based biomarkers and the epigenetic clock theory of ageing
Horvath, S., & Raj, K. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0004-3 · Cited by 3,095 · cited 1×
“Like several other welldescribed markers in blood cells, such as red cell distributionwidth (84), DNAmethylation clocks (85), and loss of Y chromosome (86), CHIP is associated with multiple adverse outcomes in epidemiological studies.”
Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776 · cited 1×
“TET2 is one of three enzymes responsible for catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and further intermediates, which can eventually lead to demethylation (49, 50).”
Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease
Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., McConkey, M., Gupta, N., Gabriel, S., Ardissino, D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1701719 · Cited by 2,683 · cited 8×
“(B) Hazard ratio (HR) and 95% confidence interval (CI) for developing CHD based on Framingham risk factors plus presence of CHIP mutations.”
BackgroundInfluentialSelf-citationFunction and information content of DNA methylation
Schübeler, D. (2015) · Nature · doi:10.1038/nature14192 · Cited by 2,060 · cited 1×
“DNMT3A is one of the two enzymes responsible for de novo methylation of the fifth position in cytosine bases of DNA, a mark that is thought to influence gene expression (47, 48).”
Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes
Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., & Ebert, B. L. (2015) · Blood · doi:10.1182/blood-2015-03-631747 · Cited by 1,971 · cited 1×
“CHIP refers to the presence of a cancer-associated variant in the blood cells of a person without a frank malignancy or another recognized clonal entity, such as monoclonal B-lymphocytosis (MBL) or paroxysmal nocturnal hemoglobinuria (40).”
Self-citationVariation in cancer risk among tissues can be explained by the number of stem cell divisions
Tomasetti, C., & Vogelstein, B. (2015) · Science · doi:10.1126/science.1260825 · Cited by 1,927 · cited 1×
“The error rate of eukaryotic DNA replication tends to be very low, except in the case where DNA mismatch repair function is compromised (10, 11) The number of replication cycles that a cell has undergone typically increases with age; therefore the number of polymerase errors also cumulatively increases (12).”
Age-related mutations associated with clonal hematopoietic expansion and malignancies
Xie, M., Lu, C., Wang, J., McLellan, M. D., Johnson, K. J., Wendl, M. C., McMichael, J. F., Schmidt, H. K., Yellapantula, V., Miller, C. A., et al. (2014) · Nature Medicine · doi:10.1038/nm.3733 · Cited by 1,874
Clinical and biological implications of driver mutations in myelodysplastic syndromes
Papaemmanuil, E., Gerstung, M., Malcovati, L., Tauro, S., Gundem, G., Van Loo, P., Yoon, C. J., Ellis, P., Wedge, D. C., Pellagatti, A., et al. (2013) · Blood · doi:10.1182/blood-2013-08-518886 · Cited by 1,832
High burden and pervasive positive selection of somatic mutations in normal human skin
Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., Wedge, D. C., Fullam, A., Alexandrov, L. B., Tubio, J. M., et al. (2015) · Science · doi:10.1126/science.aaa6806 · Cited by 1,770 · cited 1×
“An equivalent state is also pervasive in the epithelium of skin (15) and esophagus (16, 17), suggesting that somatic mutation–driven clonal expansions may be a characteristic of aging in several tissues.”
Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2
Nangalia, J., Massie, C. E., Baxter, E. J., Nice, F. L., Gundem, G., Wedge, D. C., Avezov, E., Li, J., Kollmann, K., Kent, D. G., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1312542 · Cited by 1,756 · cited 1×
“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML (65), myelodysplastic syndrome (MDS) (66–68), myeloproliferative neoplasms (69), and certain lymphomas (70, 71).”
BackgroundCloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases
Okano, M., Xie, S., & Li, E. (1998) · Nature Genetics · doi:10.1038/890 · Cited by 1,643 · cited 1×
“DNMT3A is one of the two enzymes responsible for de novo methylation of the fifth position in cytosine bases of DNA, a mark that is thought to influence gene expression (47, 48).”
Clinical Effect of Point Mutations in Myelodysplastic Syndromes
Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R. L., Neuberg, D., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1013343 · Cited by 1,627
Self-citationThe origin and evolution of mutations in acute myeloid leukemia
Welch, J. S., Ley, T. J., Link, D. C., Miller, C. A., Larson, D. E., Koboldt, D. C., Wartman, L. D., Lamprecht, T. L., Liu, F., Xia, J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.023 · Cited by 1,575 · cited 3×
“approximately one protein-coding mutation per decade of life (3).”
Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice
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., et al. (2017) · Science · doi:10.1126/science.aag1381 · Cited by 1,536 · cited 3×
“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).”
BackgroundIdentification of pre-leukaemic haematopoietic stem cells in acute leukaemia
Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., Kennedy, J. A., Schimmer, A. D., Schuh, A. C., Yee, K. W., et al. (2014) · Nature · doi:10.1038/nature13038 · Cited by 1,443
Somatic mutation in cancer and normal cells
Martincorena, I., & Campbell, P. J. (2015) · Science · doi:10.1126/science.aab4082 · Cited by 1,396
Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation
Moran-Crusio, K., Reavie, L., Shih, A., Abdel-Wahab, O., Ndiaye-Lobry, D., Lobry, C., Figueroa, M. E., Vasanthakumar, A., Patel, J., Zhao, X., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.001 · Cited by 1,339 · cited 1×
“Stem cells from these mice can grow colonies in vitro for several passages, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells (55, 56).”
Dnmt3a is essential for hematopoietic stem cell differentiation
Challen, G. A., Sun, D., Jeong, M., Luo, M., Jelinek, J., Berg, J. S., Bock, C., Vasanthakumar, A., Gu, H., Xi, Y., et al. (2012) · Nature Genetics · doi:10.1038/ng.1009 · Cited by 1,122
Somatic mutant clones colonize the human esophagus with age
Martincorena, I., Fowler, J. C., Wabik, A., Lawson, A. R. J., Abascal, F., Hall, M. W. J., Cagan, A., Murai, K., Mahbubani, K., Stratton, M. R., et al. (2018) · Science · doi:10.1126/science.aau3879 · Cited by 1,113 · cited 3×
“An equivalent state is also pervasive in the epithelium of skin (15) and esophagus (16, 17), suggesting that somatic mutation–driven clonal expansions may be a characteristic of aging in several tissues.”
Genetic and functional drivers of diffuse large B cell lymphoma
Reddy, A., Zhang, J., Davis, N. S., Moffitt, A. B., Love, C. L., Waldrop, A., Leppa, S., Pasanen, A., Meriranta, L., Karjalainen-Lindsberg, M.-L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.027 · Cited by 1,104
Tissue-specific mutation accumulation in human adult stem cells during life
Blokzijl, F., de Ligt, J., Jager, M., Sasselli, V., Roerink, S., Sasaki, N., Huch, M., Boymans, S., Kuijk, E., Prins, P., et al. (2016) · Nature · doi:10.1038/nature19768 · Cited by 935
Physiological Migration of Hematopoietic Stem and Progenitor Cells
Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L., & Weissman, I. L. (2001) · Science · doi:10.1126/science.1064081 · Cited by 933 · cited 1×
“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 (16), but there is no such spatial restriction on HSCs, which freely admix throughout the bonemarrow and body (79).”
Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia
Wong, T. N., Ramsingh, G., Young, A. L., Miller, C. A., Touma, W., Welch, J. S., Lamprecht, T. L., Shen, D., Hundal, J., Fulton, R. S., et al. (2015) · Nature · doi:10.1038/nature13968 · Cited by 892 · cited 1×
“It is hypothesized that preexistingmutantHSC clones selectively expand under the pressure of cytotoxic therapy and can cause cancer several years later with the acquisition of subsequent mutations (77).”
Coombs, C. C., Zehir, A., Devlin, S. M., Kishtagari, A., Syed, A., Jonsson, P., Hyman, D. M., Solit, D. B., Robson, M. E., Baselga, J., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.07.010 · Cited by 866 · cited 1×
“One study of a patient population treated for solid cancers found that CHIP mutations were more prevalent in this group than in populations not selected for cancer (78).”
Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells
Fraietta, J. A., Nobles, C. L., Sammons, M. A., Lundh, S., Carty, S. A., Reich, T. J., Cogdill, A. P., Morrissette, J. J. D., DeNizio, J. E., Reddy, S., et al. (2018) · Nature · doi:10.1038/s41586-018-0178-z · Cited by 862 · cited 1×
“There is also a report of an exceptional response in a patient with CLL treated by infusion of chimeric antigen receptor (CAR)– T cells in which the CAR construct disrupted one copy of TET2, while the other copy had been previously mutated somatically (97).”
Prediction of acute myeloid leukaemia risk in healthy individuals
Abelson, S., Collord, G., Ng, S. W. K., Weissbrod, O., Mendelson Cohen, N., Niemeyer, E., Barda, N., Zuzarte, P. C., Heisler, L., Sundaravadanam, Y., et al. (2018) · Nature · doi:10.1038/s41586-018-0317-6 · Cited by 850 · cited 18×
“M. A. Sanders et al., MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML.”
InfluentialRecurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis
Busque, L., Patel, J. P., Figueroa, M. E., Vasanthakumar, A., Provost, S., Hamilou, Z., Mollica, L., Li, J., Viale, A., Heguy, A., et al. (2012) · Nature Genetics · doi:10.1038/ng.2413 · Cited by 830 · cited 1×
“This was the first demonstration that mutation-driven clonal hematopoiesis occurs in healthy persons (21).”
Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6
Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., Zhao, D., Liu, Y., Wang, C., Zhang, X., et al. (2015) · Nature · doi:10.1038/nature15252 · Cited by 807 · cited 1×
“One group found that mice deficient in Tet2 developed more severe inflammation in several tissues upon challenge with bacterial endotoxin, and this was partially explained by increased expression of the proinflammatory cytokine Il6 in dendritic cells and macrophages (92).”
Mutagenic deamination of cytosine residues in DNA
Duncan, B. K., & Miller, J. H. (1980) · Nature · doi:10.1038/287560a0 · Cited by 792 · cited 1×
“The most frequent class arises from the spontaneous deamination of 5methylcytosine to thymine and primarily occurs at CpG dinucleotides, which are often in the methylated state (6).”
Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly
Zink, F., Stacey, S. N., Norddahl, G. L., Frigge, M. L., Magnusson, O. T., Jonsdottir, I., Thorgeirsson, T. E., Sigurdsson, A., Gudjonsson, S. A., Gudmundsson, J., et al. (2017) · Blood · doi:10.1182/blood-2017-02-769869 · Cited by 777 · cited 6×
“Several studies have found that CHIP is associated with a 30 to 40% increased mortality risk (28, 29, 38).”
InfluentialPrognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation
Lindsley, R. C., Saber, W., Mar, B. G., Redd, R., Wang, T., Haagenson, M. D., Grauman, P. V., Hu, Z.-H., Spellman, S. R., Lee, S. J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1611604 · Cited by 776
Self-citationKunkel, T. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.r400006200 · Cited by 754 · cited 1×
“The error rate of eukaryotic DNA replication tends to be very low, except in the case where DNA mismatch repair function is compromised (10, 11) The number of replication cycles that a cell has undergone typically increases with age; therefore the number of polymerase errors also cumulatively increases (12).”
BackgroundClonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia
Jan, M., Snyder, T. M., Corces-Zimmerman, M. R., Vyas, P., Weissman, I. L., Quake, S. R., & Majeti, R. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004315 · Cited by 721
The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia
Sperling, A. S., Gibson, C. J., & Ebert, B. L. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.112 · Cited by 706 · cited 1×
“The role of CHIP-associated genes in hematopoiesis has been extensively reviewed elsewhere (41, 42).”
Self-citationCorces-Zimmerman, M. R., Hong, W.-J., Weissman, I. L., Medeiros, B. C., & Majeti, R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1324297111 · Cited by 705
Sano, S., Oshima, K., Wang, Y., MacLauchlan, S., Katanasaka, Y., Sano, M., Zuriaga, M. A., Yoshiyama, M., Goukassian, D., Cooper, M. A., et al. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.12.037 · Cited by 699 · cited 1×
“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 (88, 89).”
Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults
Young, A. L., Challen, G. A., Birmann, B. M., & Druley, T. E. (2016) · Nature Communications · doi:10.1038/ncomms12484 · Cited by 692 · cited 3×
“Some people have clones that remain stagnant in size for many years, whereas other people have clones that show steady growth (29, 34).”
Paroxysmal nocturnal hemoglobinuria
Brodsky, R. A. (2014) · Blood · doi:10.1182/blood-2014-02-522128 · Cited by 648 · cited 1×
“The PIGA gene is required for the synthesis of glycophosphatidylinositol (GPI), and its loss results in down-regulation of several cell surface proteins that are GPI anchored (61).”
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia
Yoshizato, T., Dumitriu, B., Hosokawa, K., Makishima, H., Yoshida, K., Townsley, D., Sato-Otsubo, A., Sato, Y., Liu, D., Suzuki, H., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1414799 · Cited by 646 · cited 1×
“Clonal hematopoiesis is also commonly found in aplastic anemia, a disorder caused by an autoimmune attack on bone marrow progenitor cells that results in severely depressed blood counts (60).”
BackgroundAge-related remodelling of oesophageal epithelia by mutated cancer drivers
Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., Shiozawa, Y., Sato, Y., Aoki, K., Kim, S. K., et al. (2019) · Nature · doi:10.1038/s41586-018-0811-x · Cited by 628
Somatic mutations precede acute myeloid leukemia years before diagnosis
Desai, P., Mencia-Trinchant, N., Savenkov, O., Simon, M. S., Cheang, G., Lee, S., Samuel, M., Ritchie, E. K., Guzman, M. L., Ballman, K. V., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0081-z · Cited by 619 · cited 2×
“To refine risk estimates for developing AML associated with clonal hematopoiesis, two groups performed nested case-control studies within large population-based cohorts that had several years of follow-up (72, 73).”
Red blood cell distribution width and the risk of death in middle-aged and older adults
Patel, K. V., Ferrucci, L., Ershler, W. B., Longo, D. L., & Guralnik, J. M. (2009) · Archives of Internal Medicine · doi:10.1001/archinternmed.2009.11 · Cited by 618 · cited 1×
“Like several other welldescribed markers in blood cells, such as red cell distributionwidth (84), DNAmethylation clocks (85), and loss of Y chromosome (86), CHIP is associated with multiple adverse outcomes in epidemiological studies.”
Ko, M., Bandukwala, H. S., An, J., Lamperti, E. D., Thompson, E. C., Hastie, R., Tsangaratou, A., Rajewsky, K., Koralov, S. B., & Rao, A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112317108 · Cited by 616
Population dynamics of normal human blood inferred from somatic mutations
Lee-Six, H., Øbro, N. F., Shepherd, M. S., Grossmann, S., Dawson, K., Belmonte, M., Osborne, R. J., Huntly, B. J. P., Martincorena, I., Anderson, E., et al. (2018) · Nature · doi:10.1038/s41586-018-0497-0 · Cited by 604 · cited 2×
“(14), we estimate that by age 70, an average person without a hematological cancer will harbor 350,000”
Detectable clonal mosaicism from birth to old age and its relationship to cancer
Laurie, C. C., Laurie, C. A., Rice, K., Doheny, K. F., Zelnick, L. R., McHugh, C. P., Ling, H., Hetrick, K. N., Pugh, E. W., Amos, C., et al. (2012) · Nature Genetics · doi:10.1038/ng.2271 · Cited by 594
Detectable clonal mosaicism and its relationship to aging and cancer
Jacobs, K. B., Yeager, M., Zhou, W., Wacholder, S., Wang, Z., Rodriguez-Santiago, B., Hutchinson, A., Deng, X., Liu, C., Horner, M.-J., et al. (2012) · Nature Genetics · doi:10.1038/ng.2270 · Cited by 589 · cited 1×
“For example, copy-number gains or losses of DNMT3A, TET2, and ASXL1 are rarely found in surveys of somatic large structural variation (36).”
SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition
Kim, E., Ilagan, J. O., Liang, Y., Daubner, G. M., Lee, S. C.-W., Ramakrishnan, A., Li, Y., Chung, Y. R., Micol, J.-B., Murphy, M. E., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.006 · Cited by 575 · cited 1×
“HSCs from mice mutant for these genes, Sf3b1 (57), Srsf2 (58), and U2af1 (59), have a competitive disadvantage in vivo, unlike the clonal expansion observed in humans with these mutations.”
Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis
McKerrell, T., Park, N., Moreno, T., Grove, C. S., Ponstingl, H., Stephens, J., Crawley, C., Craig, J., Scott, M. A., Hodkinson, C., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.005 · Cited by 534
RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues
Yizhak, K., Aguet, F., Kim, J., Hess, J. M., Kübler, K., Grimsby, J., Frazer, R., Zhang, H., Haradhvala, N. J., Rosebrock, D., et al. (2019) · Science · doi:10.1126/science.aaw0726 · Cited by 500
TET2 and DNMT3A Mutations in Human T-Cell Lymphoma
Couronné, L., Bastard, C., & Bernard, O. (2012) · New England Journal of Medicine · doi:10.1056/nejmc1111708 · Cited by 494 · cited 1×
“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML (65), myelodysplastic syndrome (MDS) (66–68), myeloproliferative neoplasms (69), and certain lymphomas (70, 71).”
BackgroundBiernaux, C., Loos, M., Sels, A., Huez, G., & Stryckmans, P. (1995) · Blood · doi:10.1182/blood.v86.8.3118.3118 · Cited by 485
Wolach, O., Sellar, R. S., Martinod, K., Cherpokova, D., McConkey, M., Chappell, R. J., Silver, A. J., Adams, D., Castellano, C. A., Schneider, R. K., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan8292 · Cited by 481 · cited 2×
“Furthermore, JAK2 mutations prime neutrophils to form neutrophil extracellular traps, leading to thrombosis, whichmay also contribute to poor cardiovascular outcomes (83).”
Self-citationGibson, C. J., Lindsley, R. C., Tchekmedyian, V., Mar, B. G., Shi, J., Jaiswal, S., Bosworth, A., Francisco, L., He, J., Bansal, A., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.71.6712 · Cited by 480
Self-citationGlucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer
Wu, D., Hu, D., Chen, H., Shi, G., Fetahu, I. S., Wu, F., Rabidou, K., Fang, R., Tan, L., Xu, S., et al. (2018) · Nature · doi:10.1038/s41586-018-0350-5 · Cited by 477 · cited 1×
“However, causality could not be established, and this could represent a case of reverse causation, as hyperglycemia might influence the development or expansion of clones by interfering with TET2 function (91).”
Dorsheimer, L., Assmus, B., Rasper, T., Ortmann, C. A., Ecke, A., Abou-El-Ardat, K., Schmid, T., Brüne, B., Wagner, S., Serve, H., et al. (2019) · JAMA Cardiology · doi:10.1001/jamacardio.2018.3965 · Cited by 470 · cited 1×
“Recent evidence suggests that individuals with post-MI–related congestive heart failure who carry CHIP-associated DNMT3A or TET2 mutations have worse survival outcomes than individuals without CHIP (82).”
Miyamoto, T., Weissman, I. L., & Akashi, K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.13.7521 · Cited by 465 · cited 1×
“This was first demonstrated in a case study of a patient with AML inwhich the drivermutation of the leukemia, anAML1/ETO translocation, could be detected in a fraction of phenotypically normal HSCs and mature hematopoietic cells in remission samples (23).”
Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies
Bowman, R. L., Busque, L., & Levine, R. L. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.01.011 · Cited by 448 · cited 1×
“The role of CHIP-associated genes in hematopoiesis has been extensively reviewed elsewhere (41, 42).”
Beerman, I., Seita, J., Inlay, M. A., Weissman, I. L., & Rossi, D. J. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.04.016 · Cited by 445 · cited 1×
“Evidence from model organisms suggests that double-strand breaks may become more common as cells age (9).”
PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy
Hsu, J. I., Dayaram, T., Tovy, A., De Braekeleer, E., Jeong, M., Wang, F., Zhang, J., Heffernan, T. P., Gera, S., Kovacs, J. J., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.10.004 · Cited by 425 · cited 1×
“HSCs from mice with mutations in either Tp53 (43) or Ppm1d, a gene encoding a regulator of p53 and other members of the DNA damage response pathway (44, 45), can enter the cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.”
Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations
Loh, P.-R., Genovese, G., Handsaker, R. E., Finucane, H. K., Reshef, Y. A., Palamara, P. F., Birmann, B. M., Talkowski, M. E., Bakhoum, S. F., McCarroll, S. A., et al. (2018) · Nature · doi:10.1038/s41586-018-0321-x · Cited by 423 · cited 1×
“Instead, changes associated with chronic lymphocytic leukemia (CLL) and losses of sex chromosomes are the most common variants that accumulate in aging (37).”
Sano, S., Oshima, K., Wang, Y., Katanasaka, Y., Sano, M., & Walsh, K. (2018) · Circulation Research · doi:10.1161/circresaha.118.313225 · Cited by 417 · cited 2×
“7 macrophages and observed increased expression of Cxcl1, Cxcl2, and Il6 in response to endotoxin (88).”
BackgroundError‐Prone Repair of DNA Double‐Strand Breaks
Rodgers, K., & McVey, M. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.25053 · Cited by 407 · cited 1×
“A second class of mutation is small insertions and deletions (indels), which commonly arise from errors introduced during nonhomologous end joining of DNA double-strand breaks and can result in frameshift mutations if the breaks occur in protein-coding portions of the genome (8).”
Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host
Meisel, M., Hinterleitner, R., Pacis, A., Chen, L., Earley, Z. M., Mayassi, T., Pierre, J. F., Ernest, J. D., Galipeau, H. J., Thuille, N., et al. (2018) · Nature · doi:10.1038/s41586-018-0125-z · Cited by 406 · cited 1×
“Recent studies have implicated genetic predispositions (38, 62) as well as the microbiome (63) in the etiology and progression of clonal hematopoiesis.”
Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study
Takahashi, K., Wang, F., Kantarjian, H., Doss, D., Khanna, K., Thompson, E., Zhao, L., Patel, K., Neelapu, S., Gumbs, C., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30626-x · Cited by 399
Buscarlet, M., Provost, S., Zada, Y. F., Barhdadi, A., Bourgoin, V., Lépine, G., Mollica, L., Szuber, N., Dubé, M.-P., & Busque, L. (2017) · Blood · doi:10.1182/blood-2017-04-777029 · Cited by 383 · cited 2×
“Other studies have found links between CHIP and chronic obstructive pulmonary disease (38, 64).”
Obeng, E. A., Chappell, R. J., Seiler, M., Chen, M. C., Campagna, D. R., Schmidt, P. J., Schneider, R. K., Lord, A. M., Wang, L., Gambe, R. G., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.08.006 · Cited by 380 · cited 2×
“E. A. Obeng et al., Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation.”
BCL2 translocation frequency rises with age in humans
Liu, Y., Hernandez, A. M., Shibata, D., & Cortopassi, G. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.19.8910 · Cited by 358 · cited 1×
“01% of cells and were often transient (30, 31).”
p53-Mediated Hematopoietic Stem and Progenitor Cell Competition
Bondar, T., & Medzhitov, R. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.03.002 · Cited by 342 · cited 2×
“HSCs from mice with mutations in either Tp53 (43) or Ppm1d, a gene encoding a regulator of p53 and other members of the DNA damage response pathway (44, 45), can enter the cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.”
Gillis, N. K., Ball, M., Zhang, Q., Ma, Z., Zhao, Y., Yoder, S. J., Balasis, M. E., Mesa, T. E., Sallman, D. A., Lancet, J. E., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30627-1 · Cited by 317
Tet2 restrains inflammatory gene expression in macrophages
Cull, A. H., Snetsinger, B., Buckstein, R., Wells, R. A., & Rauh, M. J. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.08.001 · Cited by 295 · cited 1×
“Subsequent studies have confirmed the overexpression of Il6 and also found that Il1b, IL8 family chemokines, and other inflammatory mediators show increased expression in Tet2-deficient macrophages challenged with LDL or endotoxin (80, 87, 93).”
Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo
Shirai, C. L., Ley, J. N., White, B. S., Kim, S., Tibbitts, J., Shao, J., Ndonwi, M., Wadugu, B., Duncavage, E. J., Okeyo-Owuor, T., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.04.008 · Cited by 287 · cited 1×
“HSCs from mice mutant for these genes, Sf3b1 (57), Srsf2 (58), and U2af1 (59), have a competitive disadvantage in vivo, unlike the clonal expansion observed in humans with these mutations.”
BackgroundHinds, D. A., Barnholt, K. E., Mesa, R. A., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. Y., Nguyen, H. (., et al. (2016) · Blood · doi:10.1182/blood-2015-06-652941 · Cited by 267 · cited 1×
“Recent studies have implicated genetic predispositions (38, 62) as well as the microbiome (63) in the etiology and progression of clonal hematopoiesis.”
Acuna-Hidalgo, R., Sengul, H., Steehouwer, M., van de Vorst, M., Vermeulen, S. H., Kiemeney, L. A. L. M., Veltman, J. A., Gilissen, C., & Hoischen, A. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.05.013 · Cited by 264
Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 V617F Mice
Wang, W., Liu, W., Fidler, T., Wang, Y., Tang, Y., Woods, B., Welch, C., Cai, B., Silvestre-Roig, C., Ai, D., et al. (2018) · Circulation Research · doi:10.1161/circresaha.118.313283 · Cited by 262 · cited 1×
“There is also evidence that Jak2mutations in bonemarrow enhance atherosclerosis in mouse models by alteringmacrophage function (90).”
Guryanova, O. A., Shank, K., Spitzer, B., Luciani, L., Koche, R. P., Garrett-Bakelman, F. E., Ganzel, C., Durham, B. H., Mohanty, A., Hoermann, G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4210 · Cited by 256
Kahn, J. D., Miller, P. G., Silver, A. J., Sellar, R. S., Bhatt, S., Gibson, C., McConkey, M., Adams, D., Mar, B., Mertins, P., et al. (2018) · Blood · doi:10.1182/blood-2018-05-850339 · Cited by 225 · cited 1×
“HSCs from mice with mutations in either Tp53 (43) or Ppm1d, a gene encoding a regulator of p53 and other members of the DNA damage response pathway (44, 45), can enter the cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.”
Hoang, M. L., Kinde, I., Tomasetti, C., McMahon, K. W., Rosenquist, T. A., Grollman, A. P., Kinzler, K. W., Vogelstein, B., & Papadopoulos, N. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607794113 · Cited by 224
Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation
Frick, M., Chan, W., Arends, C. M., Hablesreiter, R., Halik, A., Heuser, M., Michonneau, D., Blau, O., Hoyer, K., Christen, F., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2018.79.2184 · Cited by 223 · cited 1×
“Bonemarrow 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 (96).”
Champion, K. M., Gilbert, J. G. R., Asimakopoulos, F. A., Hinshelwood, S., & Green, A. R. (1997) · British Journal of Haematology · doi:10.1046/j.1365-2141.1997.1933010.x · Cited by 171 · cited 1×
“Notably, nonrandom XCI in blood cells was observed to increase in frequency with age, although the underlying mechanism was unclear (20).”
Bonnefond, A., Skrobek, B., Lobbens, S., Eury, E., Thuillier, D., Cauchi, S., Lantieri, O., Balkau, B., Riboli, E., Marre, M., et al. (2013) · Nature Genetics · doi:10.1038/ng.2700 · Cited by 139
Fey, M., Liechti-Gallati, S., von Rohr, A., Borisch, B., Theilkas, L., Schneider, V, Oestreicher, M., Nagel, S., Ziemiecki, A., & Tobler, A. (1994) · Blood · doi:10.1182/blood.v83.4.931.931 · Cited by 138
Dnmt3a restrains mast cell inflammatory responses
Leoni, C., Montagner, S., Rinaldi, A., Bertoni, F., Polletti, S., Balestrieri, C., & Monticelli, S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616420114 · Cited by 138 · cited 1×
“For example, one study found that mast cells from mice that lacked Dnmt3a produced higher amounts of IL-6, tumor necrosis factor–a, and IL-13 in response to stimulation with immunoglobulin E in vitro, and enhanced mast cell activity was also seen in a mouse model of allergy (95).”
Sanders, M. A., Chew, E., Flensburg, C., Zeilemaker, A., Miller, S. E., Hinai, A. S. A. A., Bajel, A. R., Luiken, B., Rijken, M., McLennan, T. J., et al. (2018) · Blood · doi:10.1182/blood-2018-05-852566 · Cited by 126 · cited 1×
“The error rate of eukaryotic DNA replication tends to be very low, except in the case where DNA mismatch repair function is compromised (10, 11) The number of replication cycles that a cell has undergone typically increases with age; therefore the number of polymerase errors also cumulatively increases (12).”
Haitjema, S., Kofink, D., van Setten, J., van der Laan, S. W., Schoneveld, A. H., Eales, J., Tomaszewski, M., de Jager, S. C. A., Pasterkamp, G., Asselbergs, F. W., et al. (2017) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.116.001544 · Cited by 123 · cited 1×
“Like several other welldescribed markers in blood cells, such as red cell distributionwidth (84), DNAmethylation clocks (85), and loss of Y chromosome (86), CHIP is associated with multiple adverse outcomes in epidemiological studies.”
BackgroundCelik, H., Mallaney, C., Kothari, A., Ostrander, E. L., Eultgen, E., Martens, A., Miller, C. A., Hundal, J., Klco, J. M., & Challen, G. A. (2015) · Blood · doi:10.1182/blood-2014-08-594564 · Cited by 95 · cited 1×
“Stem cells from these mice can grow colonies in vitro for several passages, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells (55, 56).”
Cole, C. B., Russler-Germain, D. A., Ketkar, S., Verdoni, A. M., Smith, A. M., Bangert, C. V., Helton, N. M., Guo, M., Klco, J. M., O’Laughlin, S., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93041 · Cited by 84
Risk and timing of cardiovascular death among patients with myelodysplastic syndromes
Brunner, A. M., Blonquist, T. M., Hobbs, G. S., Amrein, P. C., Neuberg, D. S., Steensma, D. P., Abel, G. A., & Fathi, A. T. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017010165 · Cited by 63 · cited 1×
“Just as CHIP is associated with an increased risk of cardiovascular disease, lower-risk subtypes of MDS are also associated with a doubling of the risk of dying from cardiovascular causes (81).”
Clonal Hematopoiesis: Somatic Mutations in Blood Cells and Atherosclerosis
Natarajan, P., Jaiswal, S., & Kathiresan, S. (2018) · Circulation Genomic and Precision Medicine · doi:10.1161/circgen.118.001926 · Cited by 63 · cited 15×
“Q. Zhang et al., Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.”
InfluentialSelf-citationClonal hematopoiesis: Pre-cancer PLUS
Silver, A. J., & Jaiswal, S. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2018.12.003 · Cited by 46 · cited 1×
“The term “clonal hematopoiesis of indeterminate potential” (CHIP) was introduced to distinguish nonmalignant clonal hematopoiesis that is clearly linked to cancer-associated mutations from other forms of clonal hematopoiesis (39).”
Self-citation
Cited by
Sorted by citations
Döhner, H., Wei, A. H., Appelbaum, F. R., Craddock, C., Dinardo, C. D., Dombret, H., Ebert, B. L., Fenaux, P., Godley, L. A., Hasserjian, R. P., et al. (2022) · Blood · doi:10.1182/blood.2022016867 · Cited by 3,633
Self-citationA compendium of mutational cancer driver genes
Martínez-Jiménez, F., Muiños, F., Sentís, I., Deu-Pons, J., Reyes-Salazar, I., Arnedo-Pac, C., Mularoni, L., Pich, O., Bonet, J., Kranas, H., et al. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0290-x · Cited by 1,340
Embracing cancer complexity: Hallmarks of systemic disease
Swanton, C., Bernard, E., Abbosh, C., André, F., Auwerx, J. H., Balmain, A., Bar‐Sagi, D., Bernards, R., Bullman, S., DeGregori, J. V., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.009 · Cited by 578
Somatic mutation rates scale with lifespan across mammals
Cagan, A., Baez-Ortega, A., Brzozowska, N., Abascal, F., Coorens, T. H. H., Sanders, M. A., Lawson, A. R. J., Harvey, L. M. R., Bhosle, S., Jones, D., et al. (2022) · Nature · doi:10.1038/s41586-022-04618-z · Cited by 481
Vaiserman, A., & Krasnienkov, D. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2020.630186 · Cited by 454
“CHIP is a common aging-related phenomenon in which hematopoietic stem cells (HSCs) and other early progenitors of blood cells contribute to the formation of genetically distinct subpopulations of blood cells in aging humans (Jaiswal and Ebert, 2019).”
Background
Metadata
- Authors
- Jaiswal, S., & Ebert, B. L.
- Affiliations
- Stanford Medicine (US)
- Broad Institute (US)
- Corresponding author
- Jaiswal, Siddhartha
- Ebert, Benjamin L.
- Venue
- Science
- Published
- 2019-11
- Volume
- 366
- Issue
- 6465
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- 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
- bronze
- doi.org
- 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
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