An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis
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Clonal hematopoiesis of aging and indeterminate potential (ARCH or CHIP), driven mainly by mutations in DNMT3A and TET2, is an emerging public health issue, affecting at least 10-15% of adults older than 65 years. CHIP is associated with increased risks of de novo and therapy-related hematological neoplasms and serves as a reservoir for leukemic relapse. CHIP is also associated with increased all-cause mortality and risk of cardio-metabolic disease. The latter association may be explained, at least in part, by the effects of inactivating mutations in TET2 on progeny macrophages. We and others have shown recently that TET2-deficient macrophages are hyperinflammatory and this may exacerbate processes such as atherosclerosis. We postulated an inflammatory state associated with TET2 inactivation and/or unhealthy aging may also favor TET2-mutant hematopoietic stem and progenitor cell (HSPC) expansion. Herein, we demonstrate a clonogenic advantage for Tet2-knockout murine and TET2-mutant human HSPCs in an in vitro environment that contains the proinflammatory cytokine tumor necrosis factor-alpha (TNFα). This phenotype emerges on chronic TNFα exposure and is associated with myeloid skewing and resistance to apoptosis. To our knowledge, this is the first evidence to suggest that TET2 mutations promote clonal dominance with aging by conferring TNFα resistance to sensitive bone marrow progenitors while also propagating such an inflammatory environment. Normalizing the immune environmen…
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Tet2 and Ppm1d mutant murine models demonstrate an increased inflammatory signature in mutant macrophages, with heightened inflammatory cytokine production upon pro-inflammatory stimulation in vitro.
“Tet2 and Ppm1d mutant murine models have demonstrated an increased inflammatory signature in mutant macrophages, with heightened inflammatory cytokine production upon pro-inflammatory stimulation in vitro [31,32,69,70].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [69]
Human MDS HSPCs show significant innate immune system dysregulation and resistance to the pro-proliferative effects of inflammation.
“Human myelodysplastic syndrome (MDS) HSPCs have shown significant innate immune system dysregulation and resistance to the pro-proliferative effects of inflammation [69,80,81].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [69]
In vitro studies using murine Tet2−/− lineage marker-negative marrow cells with 24 days of TNF-α exposure show decreased apoptosis, suggesting that immature cells may better survive prolonged inflammatory stimuli.
“In vitro studies using murine Tet2−/− lineage marker-negative marrow cells with 24 days of TNF-α exposure showed decreased apoptosis [69], suggesting that the immature cells may better survive prolonged inflammatory stimuli.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [69]
Inflammation has been shown to be a driver of Tet2-mutant clonal hematopoiesis.
“inflammation has been shown to be a driver of Tet2-mutant CH.”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Abegunde et al., 2018
Tet2-deficient HSPCs show enhanced proliferation and differentiation in response to TNF-α.
“Indeed, Tet2-deficient HSPCs show enhanced proliferation and differentiation in response to microbial-induced interleukin-6 (IL-6)14 and in response to tumor necrosis factor-α (TNF-α).15”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [15]
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Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6
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Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling
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. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.03.002 · Cited by 329 · see citing works
Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling
Caiado, F., Kovtonyuk, L. V., Gonullu, N. G., Fullin, J., Boettcher, S., & Manz, M. G. (2023) · Blood · doi:10.1182/blood.2022016835 · Cited by 161 · see citing works
Clonal hematopoiesis: Mutation-specific adaptation to environmental change
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Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms
Fisher, D. A. C., Fowles, J. S., Zhou, A., & Oh, S. T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.683401 · Cited by 115 · see citing works
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Il-1r1 drives leukemogenesis induced by Tet2 loss
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Self-citation<i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i>
Zhang, C. R., Ostrander, E. L., Kukhar, O., Mallaney, C., Sun, J., Haussler, E., Celik, H., Koh, W. K., King, K. Y., Gontarz, P., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0132 · Cited by 23 · see citing works
- Authors
- Abegunde, S. O., Buckstein, R., Wells, R. A., & Rauh, M. J.
- Affiliations
- Queen's University (CA)
- Sunnybrook Health Science Centre (CA)
- Corresponding author
- Rauh, Michael J.
- Venue
- Experimental Hematology
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 59
- Pages
- 60-65
- ISSN
- 0301-472X (ISSN-L)
- OpenAlex
- W2770587365
- Cited by
- 230
- References
- 6
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 39 · 2023: 27 · 2022: 40 · 2021: 25 · 2020: 25 · 2019: 11 · 2018: 6 · 2017: 2
- FWCI
- 9.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Experimental Hematology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Queen's University
- Canada Foundation for Innovation
- Ontario Institute for Cancer Research
- Southeastern Ontario Academic Medical Organization
- Women's Giving Circle/University Hospitals Kingston Foundation
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- clonal hematopoiesis of indeterminate potential, TET2 mutation, TNF-α, inflammation, hematopoietic stem and progenitor cells, clonal dominance, myeloid skewing, apoptosis resistance, aging
- MeSH terms
- Aged, Aging, Animals, DNA-Binding Proteins, Female, Humans, Inflammation, Macrophages, Male, Mutation, Proto-Oncogene Proteins, Tumor Necrosis Factor-alpha, Apoptosis, Mice, Knockout, Dioxygenases, Mice, Stem Cell Niche
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