Aging drives Tet2 +/− clonal hematopoiesis via IL-1 signaling

In the paper

“Moreover, TET2 mutations are the most frequent single-gene mutations in myelodysplastic syndrome (MDS), an age-related hematopoietic stem and progenitor cell (HSPC) disease.9”

What the sources say

• Disputed

  The mutation table in the indexed copy (section labeled “Validations of the New Model in Different Settings”; page unavailable) lists SF3B1 in 369 patients and TET2 in 363. The paper identifies TET2 as commonly mutated, but its cohort data do not make it the most frequent single-gene mutation. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  cites [9] Nazha, 2021, Personalized prediction model to risk stratify patients with myelodysplastic syndromes, J Clin Oncol sourceExperimental — accuracy not yet measured

In the paper

“CHIP carriers have an about 13-fold increased risk of developing myeloid hematological malignancies and an increased risk of all-cause mortality, largely due to cardiovascular disease and stroke.1, 2, 3, 4”

What the sources say

• Disputed

  The Results section reports increased all-cause mortality among participants with clonal hematopoiesis (hazard ratio, 1.4). But it says the reduced survival in this cohort was explained by cancer deaths and an association with smoking, contrary to the claim that it was largely due to cardiovascular disease and stroke. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [1] Genovese, 2014, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on overall survival reports increased all-cause mortality and a higher risk of cardiovascular death among people with mutations. The cardiometabolic Results section reports increased incidence of ischemic stroke, but the Discussion says the excess mortality *may* be related to coronary heart disease and stroke. The paper does not establish that mortality was largely due to those conditions or identify stroke as a major cause of death. (LLM, conf=0.88)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section on cancer types and sample characteristics notes that 22.1% of participants were deceased at sample procurement, but does not compare mortality in carriers and noncarriers. Searches for all-cause mortality, cardiovascular disease, stroke, and survival found no passage addressing the attributed risk or causes of death. (LLM, conf=0.76)

  cites [3] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med sourceExperimental — accuracy not yet measured
• Supported

  The Clinical associations of CHIP section reports increased all-cause mortality among CHIP carriers and says the excess deaths reflected higher rates of fatal strokes and heart attacks, rather than haematological malignancies. This supports the attributed claim. (LLM, conf=0.94)

  cites [4] Jaiswal, 2019, Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease, Nat Rev Cardiol source

In the paper

“CHIP carriers have an about 13-fold increased risk of developing myeloid hematological malignancies and an increased risk of all-cause mortality, largely due to cardiovascular disease and stroke.1, 2, 3, 4”

What the sources say

• Partly supported

  The Results section ('Clonal Hematopoiesis and Subsequent Hematologic Cancer and Death'; page not provided) reports a hazard ratio of 12.9 for subsequent hematologic cancer in participants with clonal hematopoiesis. That supports the approximately 13-fold figure, but the estimate is for hematologic cancers overall, not specifically myeloid malignancies. (LLM, conf=0.86)

  cites [1] Genovese, 2014, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“Association of Somatic Mutations with the Risk of Hematologic Cancer”; page not provided) reports an 11.1-fold higher risk in people with detectable mutations. It does not report a 13-fold estimate specifically for myeloid malignancies; its estimate covers hematologic cancers more broadly. (LLM, conf=0.88)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page not provided) says clonal hematopoietic changes may contribute to hematologic malignancies, but it does not report a 13-fold risk. It explicitly says the researchers could not determine whether participants with leukemia-associated mutations later developed a malignant hematologic disease. (LLM, conf=0.85)

  cites [3] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Clinical associations of CHIP section reports an approximately tenfold increased risk of haematological cancer in CHIP carriers and says most cancers that develop are myeloid. It does not report a 13-fold estimate specifically for myeloid malignancies. (LLM, conf=0.88)

  cites [4] Jaiswal, 2019, Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease, Nat Rev Cardiol sourceExperimental — accuracy not yet measured

In the paper

“Loss-of-function heterozygous mutations in epigenetic regulators DNMT3A (cytosine methyltransferase) and TET2 (methylcytosine dioxygenase) are the most frequently detected mutations in CHIP, accounting for about 50% to 60% and 10% to 30% of mutations found in CHIP carriers, respectively.1, 2, 3,7,8”

What the sources say

• Partly supported

  The Results section (page unavailable) reports 31 TET2 mutations among 327 candidate driver mutations in participants with clonal hematopoiesis—about 9.5%, consistent with the claim’s approximate lower bound. It describes TET2 mutations as tending to disrupt protein-coding sequences, but does not establish that all 31 were loss-of-function heterozygous mutations or support a proportion approaching 30%. (LLM, conf=0.84)

  cites [1] Genovese, 2014, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports 72 TET2 variants among 805 detected mutations—about 9%—and cautions that TET2 mutations were probably undercounted because only about half the coding region was captured. It supports TET2 as a frequently mutated gene in clonal hematopoiesis, but does not establish a 10%–30% share or identify those variants collectively as heterozygous loss-of-function mutations. The indexed copy provides no page numbers for these passages. (LLM, conf=0.86)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) report TET2 mutations in 9 of 58 cases with blood-specific mutations, a proportion within the claimed 10%–30% range, and give examples of TET2 frameshift and nonsense mutations. However, the paper does not establish that all TET2 mutations counted were heterozygous loss-of-function mutations, so it does not support that more specific percentage claim. (LLM, conf=0.83)

  cites [3] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Prevalence of mutations section identifies TET2 as one of the most frequently affected genes, but reports 33.3% (134/402) of documented mutations, above the claimed 10%–30% range. The Type of mutations section lists truncating and other TET2 variants, but does not establish that heterozygous loss-of-function TET2 mutations account for the claimed proportion. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [7] Buscarlet, 2017, DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions, Blood sourceExperimental — accuracy not yet measured
• Partly supported

  The Mutational landscape of clonal haematopoiesis section says TET2 and DNMT3A mutations were the most common in the studied cohort. It does not give the claimed 10%–30% share for TET2 mutations in CHIP carriers or establish that those mutations were heterozygous loss-of-function mutations. The Determinants of clonal growth rate section discusses truncating and missense TET2 mutations but does not establish those qualifiers or the percentage. (LLM, conf=0.83)

  cites [8] Fabre, 2022, The longitudinal dynamics and natural history of clonal haematopoiesis, Nature sourceExperimental — accuracy not yet measured

In the paper

“Indeed, Tet2 loss of function in murine HSPCs leads to increased self-renewal and pool expansion, higher competitive repopulation capacity, and a predisposition to hematological malignancy development.11, 12, 13”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Ko, 2011, Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice, Proc Natl Acad Sci U S A source
• Supported

  The Results section reports expansion of the stem-cell compartment, increased self-renewal, and Tet2-deficient HSCs outcompeting wild-type cells in competitive transplants. It also reports progressive myeloproliferation in Tet2-deficient mice with features resembling human CMML, supporting the stated predisposition to hematologic malignancy. Page numbers are unavailable in our copy. (LLM, conf=0.93)

  cites [12] Moran-Crusio, 2011, Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation, Cancer Cell source
• ?Not checked — no full text of the sourcecites [13] Quivoron, 2011, TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis, Cancer Cell source

In the paper

“More important, advanced age is the best predictor of CHIP, with a 5.6% or 18.4% prevalence in the sixth or ninth decade of life, respectively.2”

What the sources say

• Partly supported

  The Results section, “Increase in the Frequency of Clonal Somatic Mutations with Age” (page not provided), reports that mutations become more frequent with age and gives the cited percentages. But 5.6% applies to ages 60–69 and 18.4% to ages 90 and older—not the sixth and ninth decades of life, respectively. The passage also does not establish that age is the best predictor relative to other factors. (LLM, conf=0.88)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured

In the paper

“Given the contribution of IL-1 to inflammaging and its detrimental impacts on WT HSC function,23,28 we further focused on the IL-1 pathway.”

What the sources say

• Supported

  The transplantation-results section reports that older WT HSCs produced myeloid-biased output, whereas older IL-1R1KO HSCs retained balanced or lymphoid-biased output. This supports a detrimental effect of IL-1 signaling on WT HSC differentiation function; the paper does not find a significant effect on engraftment or repopulation. (LLM, conf=0.88)

  cites [23] Kovtonyuk, 2022, IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice, Blood source
• Supported

  The Results section (‘Chronic IL-1 exposure impairs HSC function’) reports reduced self-renewal and regenerative function in IL-1-treated HSCs. The Discussion likewise states that chronic IL-1 exposure significantly impairs HSC function; the detrimental effect is specifically associated with chronic exposure, not acute stimulation. (LLM, conf=0.90)

  cites [28] Pietras, 2016, Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal, Nat Cell Biol source

In the paper

“Aging associates with chronic low-grade inflammation (ie, inflammaging).18,19”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Franceschi, 2000, Inflamm-aging: an evolutionary perspective on immunosenescence, Ann N Y Acad Sci source
• Supported

  The “Aging-Associated Inflammation: ‘Inflamm-Aging’” section (page not provided) describes increased inflammatory markers in healthy elderly people and defines inflamm-aging as a subclinical grade of chronic inflammation. This supports the citing sentence’s association between aging and chronic low-grade inflammation. (LLM, conf=0.93)

  cites [19] Kovtonyuk, 2016, Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment, Front Immunol source

In the paper

“HSPC divisions can be differentiating and self-renewing, particularly in less committed populations.29”

What the sources say

• Supported

  The ‘Identification of self-renewing HSCs’ section describes both self-renewing and differentiating HSC divisions. Its ‘HSC transplantation assay’ subsection contrasts the potent self-renewal of long-term HSCs with the limited reconstitution capacity of progenitor cells, supporting the emphasis on less committed populations. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [29] Wilkinson, 2020, Haematopoietic stem cell self-renewal in vivo and ex vivo, Nat Rev Genet source

In the paper

“Furthermore, progression to hematological malignancies depends on the type and complexity of mutations in CHIP.2,5,6”

What the sources say

• Partly supported

  The Results sections on mutation frequency and hematologic-cancer risk report that clonal hematopoiesis usually involved one detected mutation, whereas hematologic cancers often have multiple driver mutations; they also link detectable mutations to higher cancer risk. The paper does not establish that progression depends on mutation type or complexity: its reported risk comparisons concern mutation presence and variant allele fraction, and it could not assess whether later tumors arose from the preceding mutant clones. Page numbers were not available in our copy. (LLM, conf=0.84)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that particular mutated genes and the number of mutations affect progression risk, supporting the claim for acute myeloid leukaemia (AML). It does not establish the same relationship for haematological malignancies generally; the study’s stated outcome is progression to AML. No page number is supplied for the passage. (LLM, conf=0.86)

  cites [5] Abelson, 2018, Prediction of acute myeloid leukaemia risk in healthy individuals, Nature sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that mutation type, high allelic fractions, and clonal complexity are associated with higher risk of progression to AML; the baseline-mutations section also reports different AML risks for different mutated genes. The study addresses AML specifically, not hematological malignancies generally, and reports associations rather than establishing that progression depends on these features. (LLM, conf=0.86)

  cites [6] Desai, 2018, Somatic mutations precede acute myeloid leukemia years before diagnosis, Nat Med sourceExperimental — accuracy not yet measured

In the paper

“Loss-of-function heterozygous mutations in epigenetic regulators DNMT3A (cytosine methyltransferase) and TET2 (methylcytosine dioxygenase) are the most frequently detected mutations in CHIP, accounting for about 50% to 60% and 10% to 30% of mutations found in CHIP carriers, respectively.1, 2, 3,7,8”

What the sources say

• Partly supported

  The Results section reports 190 DNMT3A mutations among 327 candidate driver mutations in clonal hematopoiesis, or about 58%. But that count includes missense as well as disruptive mutations; the paper does not establish that 50%–60% were loss-of-function heterozygous DNMT3A mutations. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [1] Genovese, 2014, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Identification of Candidate Somatic Mutations; Increase in the Frequency of Clonal Somatic Mutations with Age; page unavailable) report 403 DNMT3A variants among 805 mutations, or about 50%, and identify DNMT3A as the most commonly mutated gene. Our copy does not establish that those DNMT3A mutations were heterozygous loss-of-function mutations, so it does not support that qualification of the percentage. (LLM, conf=0.88)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “Variants contributing to hematopoietic clonal expansion” (page unavailable), identifies DNMT3A as a recurrently mutated gene, with mutations in 18 cases. But it reports 64 blood-specific mutations in hematological-malignancy-associated genes, making the DNMT3A share about 28%, not 50%–60%. The passages also do not establish that the DNMT3A mutations were heterozygous loss-of-function mutations. (LLM, conf=0.88)

  cites [3] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘Prevalence of mutations’ section reports that DNMT3A accounts for 57.2% (230/402) of documented somatic mutations, supporting the approximate 50%–60% figure. But the ‘Type of mutations’ section includes 142 missense mutations among those 230; the paper does not establish that all mutations counted in the 57.2% are loss-of-function or heterozygous. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [7] Buscarlet, 2017, DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions, Blood sourceExperimental — accuracy not yet measured
• Partly supported

  The Mutational landscape section (page unavailable) says DNMT3A and TET2 were the most commonly mutated epigenetic regulator genes, and the Discussion (page unavailable) calls DNMT3A reportedly the most common clonal-haematopoiesis driver gene. Neither passage establishes that heterozygous loss-of-function DNMT3A mutations account for 50%–60% of mutations in CHIP carriers. (LLM, conf=0.86)

  cites [8] Fabre, 2022, The longitudinal dynamics and natural history of clonal haematopoiesis, Nature sourceExperimental — accuracy not yet measured

In the paper

“and exhibit a toll-like receptor–TNF receptor associated factor 6A (TLR-TRAF6A) and noncanonical NF-κB–dependent competitive advantage during low-grade inflammation.17”

What the sources say

• Partly supported

  The Results section on TET2-deficient HSPCs (page unavailable) reports increased myeloid contribution after competitive transplantation under low-dose LPS, preservation of Tet2-deficient HSPCs, and TRAF6-dependent activation of noncanonical NF-κB. It does not establish that the competitive advantage of Tet2-deficient HSPCs itself depends on noncanonical NF-κB; the long-term competitive-advantage experiment in the separate TLR–TRAF6-primed HSPCs section used TRAF6-overexpressing cells. (LLM, conf=0.85)

  cites [17] Muto, 2020, Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs, Nat Immunol sourceExperimental — accuracy not yet measured

In the paper

“In the context of CHIP, TET2 mutations show highest clonal expansion rates over time (with an estimated 10% annual growth rate compared with 5% of DNMT3A mutations7,8,10).”

What the sources say

• Partly supported

  The 'Effect of DNMT3A and TET2 somatic mutations on clonal expansion' section reports an estimated 9.98% yearly increase in mean variant allele frequency (VAF) for TET2, compared with 3.95% for DNMT3A—not 5%. The Discussion explains that these estimates use age at sampling as a surrogate for growth because the cohort was not resampled over time. The paper suggests TET2 may expand faster than DNMT3A, but does not establish that it has the highest rate among all CHIP mutations. (LLM, conf=0.88)

  cites [7] Buscarlet, 2017, DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions, Blood sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘Determinants of clonal growth rate’ section (page not provided) reports average annual growth of about 10% for TET2-mutant clones versus 5% for DNMT3A-mutant clones. It does not support calling TET2 the highest: SRSF2-, PTPN11- and U2AF1-mutant clones grew faster, at 15–20% per year on average. (LLM, conf=0.91)

  cites [8] Fabre, 2022, The longitudinal dynamics and natural history of clonal haematopoiesis, Nature sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [10] Watson, 2020, The evolutionary dynamics and fitness landscape of clonal hematopoiesis, Science source

In the paper

“Although alternatives have been established via adoptive transfer of unfractionated BM cells into nonirradiated mice, these models are limited by a fixed availability of BM niche space and, thus, restricted starting clonal fractions.40,41”

What the sources say

• Partly supported

  The Results (p. 2) describe transfer of unfractionated bone marrow into nonirradiated mice and report low donor-cell engraftment compared with irradiated recipients. The Discussion (p. 8) likewise describes low but stable engraftment. These passages support limited donor contribution, but do not establish that fixed availability of bone marrow niche space causes restricted starting clonal fractions. (LLM, conf=0.82)

  cites [40] Wang, 2020, Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction, JCI Insight sourceExperimental — accuracy not yet measured
• Partly supported

  STAR★METHODS, Method Details (page unavailable), describes transfer of unfractionated bone marrow cells into nonirradiated mice. The Results on age-related insulin resistance (page unavailable) report a small initial donor-cell fraction, but neither passage attributes that fraction to fixed bone-marrow niche space or states that niche space restricts starting clonal fractions. (LLM, conf=0.84)

  cites [41] Fuster, 2020, TET2-loss-of-function-driven clonal hematopoiesis exacerbates experimental insulin resistance in aging and obesity, Cell Rep sourceExperimental — accuracy not yet measured

In the paper

“Indeed, IL-1 can stimulate HSC proliferation, driving their myeloid differentiation at the expense of self-renewal, thus eroding their repopulating capacity.28,49,50”

What the sources say

• Partly supported

  The Results sections on IL-1-accelerated differentiation and chronic exposure report faster HSC division, increased myeloid differentiation, and impaired self-renewal and transplantation capacity. But the claim omits the crucial duration qualifier: the Results section on acute stimulation says acute IL-1 exposure promotes myeloid recovery without impairing HSC self-renewal. Page numbers were not provided in our copy. (LLM, conf=0.88)

  cites [28] Pietras, 2016, Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal, Nat Cell Biol sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page not supplied) reports that HSC proliferate in response to IL-1 in vitro and that IL-1RI-dependent signaling supports HSC proliferation during alum-induced granulopoiesis. It does not establish that this proliferation drives myeloid differentiation at the expense of self-renewal or erodes HSC repopulating capacity; those outcomes are not reported in the passages retrieved. (LLM, conf=0.88)

  cites [49] Ueda, 2009, IL-1R type I-dependent hemopoietic stem cell proliferation is necessary for inflammatory granulopoiesis and reactive neutrophilia, J Immunol sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report that IL-1 can induce HSC cell-cycle activity and precocious myeloid differentiation. But the Discussion emphasizes that IL-1–activated PU.1 restricts proliferation in long-term HSCs, and the passages do not establish the claimed chain from proliferation through lost self-renewal to eroded repopulating capacity. No page numbers are available in our copy. (LLM, conf=0.84)

  cites [50] Chavez, 2021, 1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress, J Exp Med sourceExperimental — accuracy not yet measured

In the paper

“and mortality from heart failure (VAF > 2%).38”

What the sources say

• Partly supported

  The Results (Prognostic Significance of CHIP in Patients With Heart Failure; page unavailable) report a dose-response association between clone size and survival, including a VAF group of at least 0.02. The Discussion says increased mortality was mainly driven by heart-failure progression. However, the clone-size analysis groups TET2 with DNMT3A; it does not establish the stated association for TET2 alone. (LLM, conf=0.84)

  cites [38] Dorsheimer, 2019, Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure, JAMA Cardiol sourceExperimental — accuracy not yet measured

In the paper

“are predicted to have high expansion rates (10% increase in mean VAF per year1, 2, 3,7)”

What the sources say

• Partly supported

  The Results section on characteristic mutations identifies disruptive TET2 mutations as candidate drivers of clonal hematopoiesis, and the Discussion reports a competitive growth advantage from TET2 loss (page numbers unavailable). Neither passage predicts a high expansion rate or a 10% annual increase in mean VAF for heterozygous TET2 loss-of-function mutations. (LLM, conf=0.85)

  cites [1] Genovese, 2014, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that TET2 loss-of-function cells have a competitive advantage in mouse models. The Results section on persistence over time (page unavailable) reports increases in variant allele fraction for some mutations, but gives no TET2-specific expansion rate. Neither passage supports the predicted 10% increase in mean VAF per year for heterozygous TET2 loss-of-function mutations. (LLM, conf=0.85)

  cites [2] Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Variants contributing to hematopoietic clonal expansion; page unavailable) associate TET2 mutations with age, and the Discussion identifies TET2 among genes involved in clonal expansion. Neither passage predicts an expansion rate for heterozygous TET2 loss-of-function mutations or reports a 10% increase in mean VAF per year. (LLM, conf=0.87)

  cites [3] Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med sourceExperimental — accuracy not yet measured
• Partly supported

  The clonal-expansion section reports a 9.98% increase in estimated mean TET2 VAF per year of age, supporting the approximate 10% figure. But it estimates this relationship across TET2 mutations generally, without establishing that the rate applies specifically to heterozygous loss-of-function mutations; the study also lacked serial resampling. (LLM, conf=0.87)

  cites [7] Buscarlet, 2017, DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions, Blood sourceExperimental — accuracy not yet measured

In the paper

“Higher TET2 mutant clone sizes associate with higher risk of progression to AML (VAF > 10%)6”

What the sources say

• Supported

  In “Mutations at any VAF are associated with increased AML risk” (page not provided), higher-VAF TET2 mutations were almost exclusively seen in AML cases. The adjusted analysis reports higher odds of developing AML for TET2 mutations at VAF ≥10% than at VAF <10%, supporting the claimed association; the paper uses ≥10%, rather than >10%, as its cutoff. (LLM, conf=0.92)

  cites [6] Desai, 2018, Somatic mutations precede acute myeloid leukemia years before diagnosis, Nat Med source

In the paper

“This likely results from a higher basal level of self-renewal, repopulation capacity, and general fitness reported in Tet2 loss-of-function HSPCs.11, 12, 13”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Ko, 2011, Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice, Proc Natl Acad Sci U S A source
• Supported

  The Results section on HSC self-renewal in vivo reports that Tet2-deficient cells outcompeted wild-type cells in competitive transplants, supporting the claim of greater repopulating capacity and competitive fitness. The Results also report increased self-renewal and serial replating of Tet2-deficient stem and progenitor cells. The paper does not use the phrase “basal level,” but the cited findings support the paraphrase. (LLM, conf=0.91)

  cites [12] Moran-Crusio, 2011, Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation, Cancer Cell source
• ?Not checked — no full text of the sourcecites [13] Quivoron, 2011, TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis, Cancer Cell source

In the paper

“in the context of CHIP, Tet2 loss-of-function mutations in myeloid cells result in increased proinflammatory responses, with reported increases in both IL-124,43 and IL-6 production,27”

What the sources say

• Supported

  The paper reports increased proinflammatory cytokine expression and IL-6 protein in TET2-deficient macrophage cultures. It also reports increased IL-1β secretion from stimulated TET2-deficient macrophages. The findings are conditional on the macrophage stimulation used in those experiments; the citing sentence does not specify those conditions. (LLM, conf=0.91)

  cites [24] Fuster, 2017, Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice, Science source
• ?Not checked — no full text of the sourcecites [43] Cull, 2017, Tet2 restrains inflammatory gene expression in macrophages, Exp Hematol source
• Supported

  The source supports the IL-6 production increase attributed to it: the Abstract reports increased IL-6 in Tet2-deficient mice, and the passage describing LPS-stimulated dendritic cells and macrophages reports increased IL-6 protein after Tet2 deficiency or knockdown. The IL-1 claim is attached to other citations, not this source. (LLM, conf=0.91)

  cites [27] Zhang, 2015, Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6, Nature source

In the paper

“Burns et al reported that progression of Tet2–/– hematopoiesis into myeloid malignancy is abrogated in the absence of Il1r1,56”

What the sources say

• Supported

  In “Il-1r1 drives leukemogenesis induced by Tet2 loss” (page not supplied), the authors state that loss of IL-1R1-dependent signaling rescues disruptions caused by Tet2 deficiency, “abrogating myeloid disease.” They also conclude that Il-1r1 loss abrogates hematological malignancy in their mouse experiments. (LLM, conf=0.91)

  cites [56] Burns, 2022, Il-1r1 drives leukemogenesis induced by Tet2 loss, Leukemia source

In the paper

“By intersecting DEGs induced by IL-1α in WT and Tet2+/− samples, we obtained DEGs that are unique to IL-1α–treated WT HSCs (221 genes), unique to IL-1α–treated Tet2+/− HSCs (318 genes), and shared by both genotypes on IL-1α treatment (515 genes; Figure 5C; supplemental Table 1).”

In the paper

“More important, terminal assessment of CD45.2+ chimerism in BM HSPCs revealed that although IL-1α–treated HSPCs were overall underrepresented, the fold reduction observed in WT HSPCs was of a much higher magnitude compared with Tet2+/− (Figure 4J).”

In the paper

“Concerning the BM HSPC frequencies, we observed a general trend for IL-1α treatment to reduce the LK compartment (Lin–c-Kit+Sca-1– cells: CMPs, granulocyte-macrophage progenitors, and megakaryocyte-erythrocyte progenitors) in both genotypes, whereas expansion of the LSK compartment (Lin–c-Kit+Sca-1+: MPP1, MPP2, and MPP3) was more evident in Tet2+/− HSPCs (Figure 4C).”

In the paper

“Principal component analysis of obtained transcriptomes revealed that in vivo PBS-treated HSC samples separate from IL-1α–treated ones, according to principal component 1, whereas IL-1α–treated WT further separate from IL-1α–treated Tet2+/− HSCs, according to principal component 2 (Figure 5B).”

In the paper

“Strikingly, IL-1α exposure resulted in a significant increase uniquely in ZsG+Tet2+/− clonal fraction in PB CD45+ leukocytes (Figure 3B), whereas this was not observed in respective controls.”

In the paper

“In detail, IL-1α exposure decreased the frequency of cells in G0 in both genotypes, although this effect was significantly stronger in Tet2+/− LT-HSCs, MPP1s, and MPP3 (Figure 4D).”

In the paper

“Interestingly, although IL-1α exposure reduced the replating capacity of HSPCs in both genotypes, the Tet2+/− HSPCs were more resistant to this effect and were able to form colonies up to the fourth replating cycle (Figure 4F)”

In the paper

“IL-1 pathway member quantification in aged WT and Tet2+/− total BM cells showed no differences in Il1r1 and Il1r2 gene expression and a decrease in Ilr1rn (IL1R antagonist) expression in Tet2+/− cells (Figure 2G).”

In the paper

“More important, Tet2+/− clonal expansion in PB leukocytes and HSPCs was further increased in animals aged for 28 months (supplemental Figure 2C-E) and in animals induced at a more advanced age (supplemental Figure 2F-H)”

In the paper

“Viability analysis showed no effect of IL-1α exposure on HSPC apoptotic levels, except for CLPs that showed decreased viability in both genotypes (supplemental Figure 4B).”

In the paper

“Moreover, although IL-1α pretreatment reduced significantly PB CD45.2+ chimerism in all lineages in both genotypes, Tet2+/− cells were more resistant to this effect (Figure 4H-I).”

In the paper

“Accordingly, we observed that IL-1α induces myeloid differentiation gene expression in both WT and Tet2+/− HSCs (with enrichment in GO BPs implicated in neutrophil biology, inflammatory response, and myeloid differentiation; Figure 5D)”

In the paper

“Tet2+/− HSCs exposed to IL-1α showed an enrichment in BPs implicated in DNA replication initiation (associated with overexpression of Mcm2-4 and 10, Cdc6, and Orc1 genes), cell cycle progression (associated with increased e2f1 expression and downstream transcriptional program), and DNA repair pathways (associated with overexpression of Rad51, Rad51b, and Fanca/i genes) (Figure 5G-I).”

In the paper

“In contrast, cell cycle analysis revealed a major impact of IL-1α exposure on HSPC proliferative responses, particularly in the LSK compartment (minor impact in LK cells; supplemental Figure 4C).”

In the paper

“Longitudinal quantification of ZsG+ WT and ZsG+Tet2+/− clonal fractions in PB CD45+ leukocytes showed that, although both clonal fractions increase over time, there was a significantly higher expansion of the Tet2+/− clone compared with the WT (Figure 2B-C).”

In the paper

“As observed in the inducible BM chimera model, IL-1α exposure led to a specific and significant expansion of CD45.2+ Tet2+/− clone size in all leukocyte lineages (Figure 3F-G) and in multiple hematopoietic progenitors (CLPs, LSKs, MPP1,3, and LT-HSCs; Figure 3H).”

In the paper

“the anakinra regimen used was not sufficient to fully prevent Tet2+/− HSPC clonal expansion (Figure 6H)”

• Also stated in: § Genetic and pharmacologic blockage of IL-1–IL-1R1 signaling reduces Tet2+/− clonal expansion during aging · hedged

  “suggesting that the anakinra treatment doses and timing used were not sufficient to revert an already established clonal dominance.”

• Also stated in: § Discussion · plain

  “IL-1R antagonist treatment prevented HSPC differentiation but did not revert an established clonal dominance in the HSPC pool.”

In the paper

“we observed 2 separate phases of Tet2+/− expansion: an initial expansion within the first 2 months after transplantation (possibly resulting from irradiation-derived inflammation), which is not observed in the inducible model; and a later expansion between months 7 and 9, which is shared with the inducible model (Figure 6C).”

In the paper

“(a) murine Tet2+/− clonal expansion rates increase with age and associate with increased BM levels of myeloid-derived inflammatory cytokine IL-1”

In the paper

“this approach revealed a Tet2+/− clonal expansion stage exclusive to advanced aged and associated with increased BM IL-1 levels”

In the paper

“Data are a pool of at least 2 independent experiments for all graphs, except J through L.”

In the paper

“Collectively, these data indicate that during aging, starting at about 7 to 8 months, there is a multilineage Tet2+/− hematopoietic clonal expansion, which associates with increased cell-extrinsic proinflammatory IL-1 levels, produced mainly by the myeloid BM compartment.”

In the paper

“Further characterization of the model revealed ZsG expression leakiness, with low expression levels in the absence of TAM injection, which was independent of sex but increased with age (up to 2.5% frequency at 10 months of age; Figure 1E).”

In the paper

“To validate the model, we exposed triple-transgenic mice to 5 consecutive injections of TAM at 100 mg/kg and observed high ZsG expression in all BM hematopoietic mature and progenitor/stem populations (range, 80%-100%) and low ZsG expression in nonhematopoietic cells (range, 3%-5%), thus confirming the relatively high hematopoietic specificity of CreERT activity”

In the paper

“Overall, these data establish the IL-1α–IL-1R1 axis as a direct driver of increased Tet2+/− multilineage differentiation, leading to Tet2+/− hematopoietic clonal fitness gain and dominance over WT hematopoiesis.”

In the paper

“Altogether, these data validate the generation of an irradiation/transplantation-independent, TAM-dose–dependent inducible, and traceable genetic chimerism model to study Tet2+/− clonal hematopoiesis.”

In the paper

“Collectively, these data demonstrate that Tet2+/− HSPCs maintain higher proliferative responses on long-term IL-1α exposure that result in a higher repopulation capacity compared with WT, thus contributing to an overall enhanced cellular competitive fitness in this setting.”

In the paper

“All mice were housed and handled according to the guidelines of the Swiss Federal Veterinary Office under specific pathogen-free conditions. All experiments were approved by the Veterinaramt Kanton Zurich (Zurich, Switzerland).”

In the paper

“This suggests that these cells are more sensitive to IL-1α–mediated proliferation and possibly less likely to return to a quiescent state after long-term IL-1α stimulation than WT.”

In the paper

“suggesting that IL-1–dependent increased proliferative activity in Tet2+/− HSPCs is both differentiating and self-renewing.”

In the paper

“TET2 heterozygous loss-of-function mutations are frequent in CHIP (about 10%-30% prevalence)”

In the paper

“IL-1 is sensed directly by the HSPC pool via IL-1R1 and favors the dominance of Tet2+/− HSPCs via enhanced proliferation and differentiation into mature blood cells, increasing Tet2+/− cell frequency over WT cells.”

In the paper

“According to our data, this IL-1–mediated proliferative response resulted in increased differentiation of Tet2+/− over WT HSPCs, leading to expansion of the Tet2+/− clone in all blood lineages.”

In the paper

“whereby the oncogenic Tet2 mutation, by endowing mutant HSPCs more resistant to the deleterious effects of high IL-1 levels, increases cellular fitness exclusively in the context of an aged and inflammatory environment, whereas the same mutation in a younger and noninflammatory milieu is less selectively expanded.”

In the paper

“These data suggest that in the context of both artificial IL-1α exposure in young mice and physiological inflammaging, Tet2+/− HSPCs show higher clonal fitness.”