The DOI matches its Crossref record; 64 of the 65 references it cites were found in a registry or an index; 25 of the 35 sources its claims cite were checked for support.
Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling
Open accessAbstract
Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras. We created Dnmt3a-mosaic mice by transplanting Dnmt3a-/- and WT HSCs into WT mice and observed the substantial expansion of Dnmt3a-/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a-/- HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a-/- clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thus demonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-function CH.
Overview
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Written from the paper’s full text.
TL;DR
Chronic *Mycobacterium avium* infection drives expansion of Dnmt3a-loss-of-function hematopoietic stem cell clones in mouse chimeras, and IFNγ signaling is necessary and sufficient for this clonal hematopoiesis. Mechanistically, Dnmt3a−/− HSCs show reduced differentiation and secondary stress-induced apoptosis, with epigenetic suppression of pro-differentiation genes.
Key findings
- In Dnmt3a-mosaic mice, chronic *M. avium* infection expanded Dnmt3a−/− HSCs; by 12 months post infection, Dnmt3a−/− cells averaged 82.8% of total HSCs in infected mice versus 19.5% in uninfected controls.
- IFNγ signaling was required and sufficient: Dnmt3a−/− Ifngr1−/− double-knockout HSCs did not expand, while daily recombinant IFNγ for one month induced Dnmt3a−/− clonal expansion; IL1β showed a trend, whereas LPS, TNFα, and pIpC did not.
- Dnmt3a−/− HSCs had reduced differentiation and less secondary stress-induced apoptosis; RNAseq showed 155 genes upregulated in WT but not Dnmt3a−/− HSCs, including Fos/Jun/Batf2, and Batf2−/− HSCs partially phenocopied Dnmt3a−/− expansion.
- Human DNMT3A−/− CD34+ HSPCs showed defective IFNγ-induced differentiation, and murine Dnmt3a−/− whole bone marrow serially replated for 8–9 rounds versus 2–3 rounds for WT; prior pIpC treatment extended Dnmt3a-mutant replating to 12 passages.
Methods
- Mouse mosaic chimeras were created by transplanting CD45.2 Dnmt3a−/− or WT whole bone marrow with CD45.1 competitor marrow into lethally irradiated CD45.1 WT recipients; mice were infected IV with 2 × 10^6 CFU *M. avium*, repeatedly for chronic infection, and analyzed by flow cytometry, colony assays, and secondary transplants.
- Functional assays included methylcellulose differentiation with IFNγ, serial replating, Annexin/Caspase-Glo apoptosis assays, cytokine bead arrays, and human CD34+ HSPC differentiation after CRISPR/Cas9 DNMT3A deletion.
- RNAseq and whole-genome bisulfite sequencing were performed on sorted HSCs; differential expression used Limma-Voom with FDR < 0.05, and a differential equation model was used to predict competing HSC population dynamics.
Limitations
- The paper states a lack of validating human data, noting the challenge of decades-long human longitudinal studies.
- The paper states that Dnmt3a−/− mice become anemic with infection, which is not a common feature of human CH, and that the phenotypes largely focus on knockout mice, giving stronger effects than heterozygous human mutations and not modeling gain-of-function mutations.
- Evident from the text: the 12-month peripheral blood analysis did not include WT:WT mosaics, and the post-transplant mosaic infection model may exaggerate competitive differences expected to take longer in non-transplant conditions.
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Claims the paper makes
33 Own interpretation · 32 Own result · 11 Partly supported · 7 Supported · 5 Own method · 2 Mixed support · 1 Not supported · 1 Couldn’t confirm · 1 Sources not found · 1 No full text of the sources · 1 Not checked yet · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“we used a Mx1-Cre+ Dnmt3af/f mouse model that approximates DNMT3A loss of function mutations commonly found in human CH (Sandoval et al., 2019).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Chronic infection promotes expansion of Dnmt3a-loss of function clones in mice.
What the sources say
- Partly supportedcites Sandoval et al., 2019 sourceExperimental — accuracy not yet measured
The Discussion and murine embryonic stem-cell results report that some DNMT3A mutations identified in AML patients reduce or abolish methyltransferase activity. The paper does not establish that such mutations are common in human clonal hematopoiesis or assess whether the Mx1-Cre+ Dnmt3af/f mouse model approximates them (pages unavailable in our copy). (LLM, conf=0.82)
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“many have noted that DNMT3A mutations confer little phenotype on steady state hematopoiesis (Buscarlet et al., 2017)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Introduction:
What the sources say
- Supportedcites Buscarlet et al., 2017 source
In “Effect of DNMT3A and TET2 mutational status on blood counts and indices” (page not specified in the supplied passage), the paper reports that DNMT3A mutation status did not affect any measured hematological end points. The Discussion likewise reports no statistically significant impact on blood counts and says blood homeostasis was maintained. (LLM, conf=0.93)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Since many CH-associated mutations themselves contribute to increased inflammatory signaling, including mutations in TET2, FLT3, JAK2, STAT1, CBL, and RAS (Azrakhsh et al., 2019; Cull et al., 2017; Jaiswal et al., 2017)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Not checked — no full text of the sourcecites Azrakhsh et al., 2019 source
- Not checked — no full text of the sourcecites Cull et al., 2017 source
- Partly supportedcites Jaiswal et al., 2017 sourceExperimental — accuracy not yet measured
The Results (page not provided) show increased inflammatory chemokines and cytokines in Tet2-deficient macrophages, supporting the TET2 portion. The Discussion explicitly says it is unclear whether JAK2 mutations increase coronary risk through inflammation, and the passages found do not establish inflammatory signaling for FLT3, STAT1, CBL, or RAS. (LLM, conf=0.90)
plaindirect- 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.
Every source the paper cites for this claim was checked and supports it.
In the paper
“many alterations in genome methylation occurred in bivalent canyon sites that have been associated previously with developmentally important genes (Jeong et al., 2014).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Supportedcites Jeong et al., 2014 source
The Results section on histone modifications identifies Canyons bearing both H3K27me3 and H3K4me3 as bivalent-like and associates them with developmentally important genes. The Results section on Dnmt3a reports methylation changes at Canyon edges in knockout hematopoietic stem cells and says Canyons bearing both marks were more likely to contract. The claim is supported in that experimental context. (LLM, conf=0.88)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a recently published study examining gene expression differences between serially transplanted Dnmt3a−/− HSCs and WT HSCs, these genes are also differentially suppressed in the Dnmt3a−/− cells”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Partly supportedcites Jeong et al., 2018 sourceExperimental — accuracy not yet measured
The Results section, “Dnmt3a Controls DNA Methylation at HSC Regulatory Elements” (page unavailable), reports RNA-seq comparisons of control and serially transplanted Dnmt3aKO HSCs and says genes in bivalent canyons showed repression with extended passage. The citing sentence does not identify what “these genes” refers to, so our copy cannot establish that the particular genes intended were suppressed. (LLM, conf=0.78)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“thus supporting the concept that management of acute and chronic inflammatory conditions including infections may modify risk for clonal expansion and subsequent malignancy (Binder et al., 2018; Mantovani et al., 2018).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Not checked — no full text of the sourcecites Binder et al., 2018 source
- Partly supportedcites Mantovani et al., 2018 sourceExperimental — accuracy not yet measured
The Introduction links chronic inflammatory conditions, including infection, to increased cancer risk. The Concluding remarks say IL-1 targeting may affect cancer incidence, supporting the possibility that managing inflammation could modify malignancy risk. The paper does not extend that conclusion to management of acute infections or describe a resulting change in clonal expansion. (LLM, conf=0.85)
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.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“suggesting that infection is likely not the only chronic stress or source of chronic inflammation that contributes to their regulation (Jeong et al., 2018).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Could not verifycites Jeong et al., 2018 sourceExperimental — accuracy not yet measured
The Results section on HSC regulatory elements describes gene-expression changes after Dnmt3a loss, but does not link those changes to infection or other chronic inflammatory stresses. Searches for infection, chronic inflammation, and chronic stress found no passage in our copy addressing whether such stresses regulate the genes. (LLM, conf=0.74)
hedgedconditional- 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.
- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the bone marrow, the percentage of total HSCs that were Dnmt3a−/− reached an average of 82.8% in the infected mosaic mice by 12 months after infection, compared to 19.5% for the uninfected controls (Figure 2H–I, S2B).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Chronic infection promotes Dnmt3a−/− clonal hematopoiesis in the peripheral blood of mice.
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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Predictably, the effect size was smaller than that seen for Dnmt3a−/− HSCs.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Chronic infection promotes expansion of Dnmt3a-loss of function clones in mice.
plain- 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.
A result the paper reports from its own data — 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 Dnmt3a−/− HSCs from both naïve and infected mosaics showed strong long-term engraftment (Figure 3H).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a−/− HSCs show reduced differentiation and secondary stress-induced apoptosis in response to infection.
boosted- 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. 21
- It may state two separate claims as one. 18
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“inflammation has been shown to be a driver of Tet2-mutant CH.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Introduction:
What the sources say
- Not checked — no full text of the sourcecites Abegunde et al., 2018 source
- Supportedcites Cai et al., 2018 source
The Results (page unavailable in our copy) report that LPS-induced inflammation increased the ratio of Tet2-KO to wild-type cells in a mouse model of clonal hematopoiesis, while anti-inflammatory treatment repressed Tet2-KO cell expansion. This directly supports inflammation as a driver of Tet2-mutant clonal hematopoiesis in the studied model. (LLM, conf=0.93)
- Disputedcites Fuster et al., 2017 sourceExperimental — accuracy not yet measured
The paper reports the opposite causal direction: TET2 deficiency increases inflammatory cytokine production, while clonal expansion of TET2-deficient cells contributes to atherosclerosis. In the indexed passage labeled Abstract (page unavailable), NLRP3 inhibition reduced atherosclerosis but “did not affect the expansion of TET2-deficient cells”; it does not show inflammation driving that expansion. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
boosteddirect- 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.
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Both NR4A1 and SOCS3 have been noted to play a role in supporting HSC homeostasis by dampening inflammatory responses (Freire and Conneely, 2018; Kim et al., 2017).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Supportedcites Freire and Conneely, 2018 source
The Discussion (page not supplied) says NR4A receptors help maintain HSC quiescence and suppress inflammatory responses, including NF-κB-driven signaling. In this jointly cited sentence, Freire and Conneely support the NR4A1 portion; the SOCS3 portion is not attributed specifically to this paper. (LLM, conf=0.90)
- Disputedcites Kim et al., 2017 sourceExperimental — accuracy not yet measured
The Results and discussion section, “Level of Socs3 expression dictates HSC homeostasis in the BM” (page unavailable), reports that Socs3 overexpression impairs HSC homeostasis—the opposite of the role attributed to SOCS3 here. The Concluding remarks instead link preserved homeostasis to repression of Socs3 and discuss Tpo/Jak2 signaling, not dampening inflammatory responses. This paper does not address NR4A1. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
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: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Strikingly, loss of the histone demethylase Kdm6b leads to opposite effects on Fos and Jun”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Disputedcites Mallaney et al., 2019 sourceExperimental — accuracy not yet measured
The Results section (page not supplied) says that both Fos and Jun were overexpressed in Kdm6b-deficient hematopoietic stem cells, at baseline and more strongly under stress. It therefore reports effects in the same direction, not opposite effects. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
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: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“DNMT3A, the gene most commonly mutated in CH”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Introduction:
What the sources say
- Partly supportedcites Young et al., 2016 sourceExperimental — accuracy not yet measured
The Results (Error-corrected NGS; page unavailable) report that 64% of exonic clonal variants occurred in DNMT3A and TET2 combined. The Discussion says DNMT3A mutations are frequent in clonal haematopoiesis, but the paper does not establish that DNMT3A alone is the most commonly mutated gene. (LLM, conf=0.84)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“mutations in DNMT3A, the gene most commonly mutated in CH, are nearly universal in individuals by the age of 50 (Young et al., 2016)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Introduction:
What the sources say
- Partly supportedcites Young et al., 2016 sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports clonal haematopoiesis in 95% of the healthy 50–60-year-olds studied, with mutations frequently in DNMT3A or TET2. The Results (Error-corrected NGS; page unavailable) show DNMT3A is a frequent mutation site, but the paper does not say DNMT3A mutations themselves are nearly universal, or establish that they are present by age 50. (LLM, conf=0.90)
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.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Dnmt3a loss of function mutations, which comprise the majority of human CH-associated mutations (Russler-Germain et al., 2014)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Introduction:
What the sources say
- Partly supportedcites Russler-Germain et al., 2014 sourceExperimental — accuracy not yet measured
The Discussion describes DNMT3A mutations that impair its function, and the Introduction reports DNMT3A mutation frequencies in acute myeloid leukemia (AML). Neither passage establishes that DNMT3A loss-of-function mutations comprise the majority of mutations associated with human clonal hematopoiesis; the reported population is AML, not clonal hematopoiesis. (LLM, conf=0.83)
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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“prior studies showed that Dnmt3a−/− HSCs demonstrate defective differentiation and enhanced self-renewal (Challen et al., 2011; Jeong et al., 2018)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Introduction:
What the sources say
- Supportedcites Challen et al., 2011 source
The Results section, “Dnmt3a loss impairs long-term HSC differentiation in vivo,” reports that Dnmt3a-null HSCs’ differentiation capacity declined sharply during serial transplantation while their self-renewal potential increased and remained sustained. This supports both parts of the attributed claim. (LLM, conf=0.94)
- Supportedcites Jeong et al., 2018 source
In Results, the paper reports that Dnmt3aKO HSCs failed to generate substantial peripheral-blood progeny after the third transplant, yet repopulated bone marrow through 12 transplant rounds; it says this self-renewal far exceeds that of normal HSCs. A separate Results section reports severely compromised myeloid differentiation in late-passage Dnmt3aKO HSCs. Page numbers were not provided in our copy. (LLM, conf=0.94)
boosteddirect- 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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Nr4a1 has been reported to be reduced in Dnmt3a-mutant hematopoietic progenitors”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Supportedcites Kramer et al., 2017 source
The Results section ('Nr4a1 is downregulated in Dnmt3aKO DN2 thymic progenitors') reports 2.3-fold lower Nr4a1 expression in Dnmt3aKO DN2 cells and also reports downregulation in Dnmt3aKO early thymic progenitors. These are the hematopoietic progenitors supporting the citing sentence. (LLM, conf=0.91)
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: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“although increased red cell distribution width (RDW) has been reported (Jaiswal et al., 2014).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion: > Limitations of the Study:
What the sources say
- Supportedcites Jaiswal et al., 2014 source
The Results section, “Blood-Cell Indexes of Persons with Somatic Mutations,” reports significantly higher red-cell distribution width in participants with detectable somatic mutations than in those without mutations (13.8% vs. 13.4% among normocytic subjects). This supports the claim that increased RDW has been reported in humans with clonal hematopoiesis. (LLM, conf=0.94)
plaincorrelational- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“leading to suppression of apoptosis (Kramer et al., 2017).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Partly supportedcites Kramer et al., 2017 sourceExperimental — accuracy not yet measured
The Discussion says Dnmt3aKO-derived DN2 thymic progenitors have reduced apoptosis partially due to Nr4a1 downregulation. The claim omits “partially” and extends this finding from DN2 thymic progenitors to Dnmt3a-mutant hematopoietic progenitors generally. (LLM, conf=0.86)
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: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While hypermethylation in the setting of a Dnmt3a deletion seems counterintuitive, it has also been reported in other studies”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Supportedcites Jeong et al., 2018 source
The Results section (‘Dnmt3a Controls DNA Methylation at HSC Regulatory Elements’) reports increased DNA methylation in bivalent and inactive canyons of Dnmt3a-knockout HSCs. This supports the claim that hypermethylation has been observed following Dnmt3a deletion, even though the paper also reports overall hypomethylation. (LLM, conf=0.93)
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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“suggesting an interrelated regulatory mechanism (Mallaney et al., 2019).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Partly supportedcites Mallaney et al., 2019 sourceExperimental — accuracy not yet measured
The Results and Discussion report that Kdm6b loss dysregulates Fos and Jun in hematopoietic stem cells, and that reducing their expression improves engraftment. They do not establish an interrelated regulatory mechanism involving Dnmt3a loss; searches for Dnmt3a and the proposed mechanism found no supporting passage. The Discussion also says the mechanism linking Kdm6b and AP-1 remains unclear. Page numbers were not available in our copy. (LLM, conf=0.86)
hedgedcorrelational- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Aging itself is associated with increased inflammation (Piber et al., 2019)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Supportedcites Piber et al., 2019 source
The Abstract states that systemic inflammation increases with age. The Discussion also reports higher levels of specific inflammatory markers with increasing age among adults over 60, while noting that other markers were not significantly associated with age. (LLM, conf=0.94)
plaincorrelational- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“and may be related to compensatory effects of alternative methyltransferases (Jeong et al., 2018).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Partly supportedcites Jeong et al., 2018 sourceExperimental — accuracy not yet measured
The Results section, “Dnmt3a Controls DNA Methylation at HSC Regulatory Elements” (page unavailable), reports hypermethylated regions in Dnmt3a-knockout HSCs, including increased methylation in bivalent and inactive canyons. It does not attribute that hypermethylation to compensatory activity by alternative methyltransferases, so the proposed explanation is unsupported by our copy. (LLM, conf=0.84)
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.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Immune signaling pathways are known to contribute to DNMT3A-associated hematologic conditions including aplastic anemia, myeloproliferative neoplasms, myelodysplastic syndrome, and acute myelogenous leukemia (Azrakhsh et al., 2019; Jacquelin et al., 2018; Yoshizato et al., 2015).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
What the sources say
- Not checked — no full text of the sourcecites Azrakhsh et al., 2019 source
- Not checked — no full text of the sourcecites Jacquelin et al., 2018 source
- Partly supportedcites Yoshizato et al., 2015 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) links DNMT3A-mutated clones in aplastic anemia to progression toward MDS/AML, and the paper describes aplastic anemia as immune-mediated. It does not establish that immune signaling pathways contribute to DNMT3A-associated disease across the listed conditions or address that mechanism in myeloproliferative neoplasms. The Discussion instead says it is unlikely that DNMT3A-mutated clones initiate a pathogenic immune response. (LLM, conf=0.86)
boostedcorrelational- 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.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Whereas the percentage of Dnmt3a−/− CD45.2 peripheral blood mononuclear cells (PBMCs) expanded to an insignificant degree in this time frame for naïve mice, the percentage increased significantly for infected mosaic mice at both 8- and 12-months post infection (Figure 2B–G).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Chronic infection promotes Dnmt3a−/− clonal hematopoiesis in the peripheral blood of mice.
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 result the paper reports from its own data — 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 total number of differentially expressed genes was lower in the Dnmt3a−/− background than WT (Figure 6D), with 155 genes upregulated in WT but not Dnmt3a−/− HSCs.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a loss of function blunts HSC response to infection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whereas HSCs were depleted upon chronic repeated infection of WT mice, the number of HSCs remained relatively intact in Batf2 KO mice, similar to the protection observed in chronically infected Dnmt3a−/− mice (Figure 3F).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a loss of function blunts HSC response to infection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Figure 5C, Dnmt3a−/− clonal expansion occurred as expected upon M. avium infection, but no clonal expansion was evident among mosaics with the DKO minor population or in mosaic mice with a minor population of Ifngr1−/− HSCs.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a loss of function blunts HSC response to infection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Whereas infection significantly altered gene expression in WT HSCs, there were fewer differences in the Dnmt3a−/− background (Figure 6A, 6B, Supplemental Tables 2–3).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a loss of function blunts HSC response to infection.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At low concentrations (1 ng/mL), IFNγ stimulated increased WT colony formation, whereas this increase was diminished for Dnmt3a−/− HSCs (Figure 4B, S4C).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Human and murine Dnmt3a-mutant HSPCs show decreased differentiation and increased serial replating capacity under inflammatory stress.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PIPC treatment slightly augmented the serial replating capacity of Dnmt3a-mutant WBM (compare maroon to orange), extending the potential for replating from 9 to 12 passages.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Human and murine Dnmt3a-mutant HSPCs show decreased differentiation and increased serial replating capacity under inflammatory stress.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Upon IFNγ stimulation, control CD34+ cells differentiated at a high rate, as indicated by a loss of CD34+ CD38− HSCs and a significant increase in CD38+ progenitors and CD66b+ neutrophils. In contrast, DNMT3A−/− human CD34+ cells did not differentiate normally, showing little change in either their HSC or neutrophil numbers after three days in culture with IFNγ (Figure 4F).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Human and murine Dnmt3a-mutant HSPCs show decreased differentiation and increased serial replating capacity under inflammatory stress.
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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At high concentrations (100 ng/mL), IFNγ resulted in a loss of total WT colonies, whereas Dnmt3a−/− HSCs were relatively resistant to these toxic effects (Figure 4A, S4B).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Human and murine Dnmt3a-mutant HSPCs show decreased differentiation and increased serial replating capacity under inflammatory stress.
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 result the paper reports from its own data — 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, daily injection of IL1β induced a clear trend toward expansion, whereas no trend was observed in the setting of daily LPS, TNFa, or polyinosinic-polycytidylic acid (pIpC) treatment (Figure 5E).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a loss of function blunts HSC response to infection.
boosteddirect- 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
“Collectively, these experiments indicate that sustained IFNγ signaling is necessary and sufficient to induce infection-associated Dnmt3a−/− HSC expansion.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a loss of function blunts HSC response to infection.
hedgeddirect- 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
“we did not see expansion among more downstream populations such as granulocyte-monocyte progenitors, megakaryocyte progenitors, or B and T cells, macrophage/monocytes, or granulocytes (Figures S1E–L), suggesting a differentiation block in the Dnmt3a-mutant population at the level of the MPP.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Chronic infection promotes expansion of Dnmt3a-loss of function clones in mice.
hedged- 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
“Collectively, these studies indicate that the phenotypically defined Dnmt3a−/− HSCs that expand upon infection remain functional in long-term reconstitution studies, are more resistant to loss by secondary stress-induced apoptosis and differentiation, and retain their self-renewal capacity better than WT HSCs when stressed by chronic infection with M. avium.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a−/− HSCs show reduced differentiation and secondary stress-induced apoptosis in response to infection.
hedgeddirectn = 250- 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
“Collectively, these experiments show that Dnmt3a−/− HSCs have improved survival at high IFNγ concentrations and reduced differentiation at low IFNγ concentrations, both of which may contribute to a survival advantage.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Human and murine Dnmt3a-mutant HSPCs show decreased differentiation and increased serial replating capacity under inflammatory stress.
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Quality control was conducted using FastQC (Andrews, 2010) and CGmapTools (Guo et al., 2018).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > METHOD DETAILS
What the sources say
- Not matchedcites Andrews, 2010
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites Guo et al., 2018 source
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.
- Not matched
In the paper
“there have been recent reports of human epidemiologic data correlating CH with severe infections (Bolton et al., 2020a)”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion: > Limitations of the Study:
What the sources say
- Not matchedcites Bolton et al., 2020a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- 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.
- Not matched
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
“Our controlled biological experiments provide proof of concept that an infection can promote Dnmt3a-loss of function CH through increased resistance to stress-induced apoptosis and a defect in differentiation, driven by impaired expression of an IFNγ-dependent transcriptional network (Figure S7).”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
boosteddirect- 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
“Differentially methylated regions (DMRs) were identified with CGmapTools (Guo et al., 2018) using all CG sites with a minimum of 4x and maximum of 100x coverage and Benjamini & Hochberg correction for multiple testing.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > METHOD DETAILS
What the sources say
- Not checked — no full text of the sourcecites Guo et al., 2018 source
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.
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
“We find that inflammatory IFNγ signaling is both necessary and sufficient for Dnmt3a-loss of function CH.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To check the efficiency of deletion at the end of the experiment, CD45.2+ HSCs from mock-infected and infected mosaic mice were sorted into StemSpan media (Stem Cell Technologies), incubated for 2 weeks, and then the colonies were genotyped.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > METHOD DETAILS
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each experimental replicate was conducted with cells from a different biological sample, representing a different individual.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > METHOD DETAILS
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.
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
“Our findings lend further support to the emerging theme that inflammation is a major driver of both aging and age-associated CH”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion:
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Gene deletion was confirmed by PCR and realtime using the following primers”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > METHOD DETAILS
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.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The phenotypes reported in this study largely focus on KO mice”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Discussion: > Limitations of the Study:
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.
The paper relies on this without support.
Age and smoking are both associated with inflammation.
“given that age and smoking are both associated with inflammation”
The paper relies on this without support.
Specific environmental drivers of DNMT3A-mutant clonal hematopoiesis have not been determined.
“specific environmental drivers of DNMT3A-mutant CH have not been determined.”
The paper relies on this without support.
BATF2 is a critical IFNγ-induced transcription factor that drives myeloid differentiation of HSCs.
“As a case in point, we previously identified BATF2 to be a critical IFNγ-induced transcription factor that drives myeloid differentiation of HSCs.”
The paper relies on this without support.
Anemia is not a common feature of humans with CH.
“but this is not a common feature of humans with CH although increased red cell distribution width (RDW) has been reported (Jaiswal et al., 2014).”
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 cited source doesn’t support the claim as written.
In the citing paper
“Although the competitive advantage of Dnmt3a-mutant HSCs during inflammation has been implied (20,23), no direct experiments have been performed to quantify fitness between mutant and WT HSCs in response to IFNγ.”
From Txnip Enhances Fitness of Dnmt3a -Mutant Hematopoietic Stem Cells via p21 (2022) · cites this paper as [20]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“supporting that IFN-γ signaling is necessary and sufficient for the fitness of Dnmt3a knockout hematopoiesis.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“However, in competitive transplantation into recipient wild-type mice without additional stimuli, the advantage of Dnmt3a mutant cells is not significant and is only apparent in the context of chronic Mycobacterium avium (M. avium) infection [49].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“The competitive advantage of Dnmt3a-mutant HSCs is exacerbated by hematopoietic stress such as serial transplantation (19) and microbial infection (20).”
From Txnip Enhances Fitness of Dnmt3a -Mutant Hematopoietic Stem Cells via p21 (2022) · cites this paper as [20]
The cited source says what the claim attributes to it.
In the citing paper
“There is emerging evidence that clonal HSCs can become inflammation-adapted47–49 and by altering the response to inflammatory challenges, mutations can thus confer a fitness advantage to HSCs.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [48]
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
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > RESOURCE AVAILABILITY
“Formulas used to calculate mathematical predictions in Supplemental Figures 2C–F are available in Supplementary Table 1.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > Results: > Dnmt3a−/− HSCs show reduced differentiation and secondary stress-induced apoptosis in response to infection.
“we could predict that a minor population of Dnmt3a−/− HSCs would overtake a major population of WT HSCs in the presence of chronic infection (Figures S3C–F).”
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
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > RESOURCE AVAILABILITY
“This study did not generate new unique reagents.”
§ Chronic Infection drives Dnmt3a-Loss of function Clonal Hematopoiesis via IFNg signaling > STAR METHODS > EXPERIMENTAL MODEL AND SUBJECT DETAILS
“Batf2-KO mice were generated in conjunction with the genetically engineered mouse core facility at BCM by the use of CRISPR gene editing to remove exons 1 and 2 of Batf2 in a C57BL/6 background.”
Citations
Cites
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Age-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
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
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Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease
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Age-related mutations associated with clonal hematopoietic expansion and malignancies
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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
Asymmetric and symmetric stem-cell divisions in development and cancer
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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
Self-citationVisualizing Genomic Data Using Gviz and Bioconductor
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Cited by
Sorted by citations
Items 101–200 of 329
Nielsen, A. B., Hansen, J. W., Ørskov, A. D., Dimopoulos, K., Salem, M., Grigorian, M., Brüünsgaard, H., & Grønbæk, K. (2022) · HemaSphere · doi:10.1097/hs9.0000000000000713 · Cited by 19
Causes of Clonal Hematopoiesis: a Review
Joo, L., Bradley, C. C., Lin, S. H., Scheet, P. A., & Nead, K. T. (2023) · Current Oncology Reports · doi:10.1007/s11912-023-01362-z · Cited by 23
Clonal hematopoiesis and inflammation: A review of mechanisms and clinical implications
Nathan, D. I., Dougherty, M. L., Bhatta, M., Mascarenhas, J. O., & Marcellino, B. K. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.104187 · Cited by 22
Usart, M., Stetka, J., Paz, D. L., Hansen, N., Kimmerlin, Q., Fonseca, T. A., Lock, M., Kubovčáková, L., Karjalainen, R., Hao-Shen, H., et al. (2024) · Blood · doi:10.1182/blood.2023020270 · Cited by 22
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Metadata
- Authors
- Hormaechea-Agulla, D., Matatall, K. A., Le, D. T., Kain, B., Long, X., Kus, P., Jaksik, R., Challen, G. A., Kimmel, M., & King, K. Y.
- Affiliations
- Baylor College of Medicine (US)
- Rice University (US)
- Silesian University of Technology (PL)
- Washington University in St. Louis (US)
- Corresponding author
- King, Katherine Y.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 28
- Issue
- 8
- Pages
- 1428-1442.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC8349829
- OpenAlex
- W3138449921
- Cited by
- 329
- References
- 65
- Citations by year
- 2026: 43 · 2025: 66 · 2024: 63 · 2023: 68 · 2022: 64 · 2021: 25
- FWCI
- 36.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01HL134880, R01HL136333, T32AI053831, T32DK060445, T32HL092332)
- National Institute of Allergy and Infectious Diseases (AI036211, P30CA125123, S10 OD020066)
- National Center for Research Resources (S10RR024574)
- Baylor College of Medicine (NCI-CA125123, NIDDK-DK56338, P30 CA125123)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Blood disorders and treatments
- Keywords
- clonal hematopoiesis, DNMT3A, loss-of-function mutations, chronic infection, mycobacterial infection, interferon-gamma signaling, hematopoietic stem cells, clonal expansion, DNA methylation, epigenetic modifications, apoptosis, age-related diseases, somatic mutations, mouse chimeras
- MeSH terms
- Clonal Hematopoiesis, Animals, DNA (Cytosine-5-)-Methyltransferases, Hematopoiesis, Hematopoietic Stem Cells, Mutation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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