Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis
Abstract
Clonal hematopoiesis results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. We developed a technique that combines mosaic mutagenesis with color labeling of HSPCs to study how acquired mutations affect clonal fitness in a native environment. Mutations in clonal hematopoiesis–associated genes such as asxl1 promoted clonal dominance. Single-cell transcriptional analysis revealed that mutations stimulated expression of proinflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone. Biallelic loss of one such immunomodulator, nr4a1 , abrogated the ability of asxl1- mutant clones to establish clonal dominance. These results support a model where clonal fitness of mutant clones is driven by enhanced resistance to inflammatory signals from their mutant mature cell progeny.
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Clonal hematopoiesis increases in prevalence with age and is associated with increased risk of hematologic malignancies and cardiovascular disease, likely through inflammatory effects of mutant cells.
“Clonal expansion of blood cells, called clonal hematopoiesis (CH), increases in prevalence with age and is associated with increased risk of hematologic malignancies, but also unexpectedly with increased risk of cardiovascular disease20,21, likely through inflammatory effects of mutant cells22.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [22]
A zebrafish model of CH identified increased expression of pro-inflammatory cytokines, including Il1b and Tnfb, in mutant macrophages isolated from the marrow compared to macrophages from control animals.
“This model identified increased expression of pro-inflammatory cytokines, including Il1b and TNF superfamily member Tnfb, in mutant macrophages isolated from the marrow compared to macrophages from control animals [71].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [71]
In a zebrafish TWISTR model, homozygous loss of nr4a1 in asxl1 mutant clones prevented clonal growth.
“Using TWISTR, the authors showed that homozygous loss of nr4a1 in asxl1 mutant clones prevented clonal growth, suggesting that NR4A1 is necessary for clonal expansion [71].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [71]
In mutant zebrafish hematopoietic stem and progenitor cells, overexpression of socs3a, atf3, and nr4a1 was found, and these molecules were critical for regulating intracellular inflammatory responses.
“When comparing the transcriptional profile of HSPCs in mutant zebrafish to control animals, the authors found overexpression of several molecules, such as socs3a, atf3, and nr4a1, that were critical for regulating the intracellular inflammatory responses.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [71]
NR4A1 is necessary for clonal expansion.
“Using TWISTR, the authors showed that homozygous loss of nr4a1 in asxl1 mutant clones prevented clonal growth, suggesting that NR4A1 is necessary for clonal expansion [71].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [71]
In a zebrafish model of clonal hematopoiesis using TWISTR, a survival pathway within mutant hematopoietic stem and progenitor cells involving inflammatory modulators was identified.
“A zebrafish model of CH using an approach called TWISTR (tissue editing with inducible stem cell tagging via recombination) identified a survival pathway within the mutant HSPCs involving inflammatory modulators [71].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [71]
There is emerging evidence that clonal HSCs can become inflammation-adapted and by altering the response to inflammatory challenges, mutations can thus confer a fitness advantage to HSCs.
“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 [49]
Isolated effects of individual inflammatory cytokines, including type 1 interferons (IFNa/b), type 2 IFN (IFNg), TNFa, and IL-1, have been well-documented in mouse hematopoietic development.
“The isolated effects of individual inflammatory cytokines, including type 1 interferons (IFNa/b) 1-3 , type 2 IFN (IFNg) 4-6 , TNFa 7,8 , and IL-1 9-11 , have been well-documented in mouse hematopoietic development.”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [4]
These cytokines display overlapping features, such as inducing cell cycle entry of HSCs and their differentiation, frequently toward the granulo-monocytic lineage.
“These cytokines display overlapping features, such as inducing cell cycle entry of HSCs and their differentiation, frequently toward the granulo-monocytic lineage 1,4-6,12-15 .”
From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [4]
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- Authors
- Avagyan, S., Henninger, J. E., Mannherz, W. P., Mistry, M., Yoon, J., Yang, S., Weber, M. C., Moore, J. L., & Zon, L. I.
- Affiliations
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
- Whitehead Institute for Biomedical Research (US)
- Harvard University (US)
- Boston Children's Hospital (US)
- Corresponding author
- Avagyan, S.
- Henninger, J. E.
- Zon, L. I.
- ORCID
- Venue
- Science
- Published
- 2021-11-05
- Volume
- 374
- Issue
- 6568
- Pages
- 768-772
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3209858224
- Semantic Scholar
- fec8a839b4dffcd9b9107e58604ae83169b17beb
- Cited by
- 192
- References
- 32
- Citations by year
- 2026: 24 · 2025: 39 · 2024: 50 · 2023: 42 · 2022: 36
- FWCI
- 21.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01 HL131477, F31 HL126338)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- clonal hematopoiesis, clonal fitness, anti-inflammatory factors, hematopoietic stem cells, clonal dominance, zebrafish model, hematologic disorders, cancer risk, hematopoietic progenitor cells
- MeSH terms
- RNA-Seq, Clonal Hematopoiesis, Animals, DNA (Cytosine-5-)-Methyltransferases, Hematopoietic Stem Cells, Inflammation, Mutation, Repressor Proteins, Selection, Genetic, Zebrafish, Genes, p53, Cytokines, Frameshift Mutation, Myeloid Cells, Zebrafish Proteins, Nuclear Receptor Subfamily 4, Group A, Member 1, Single-Cell Analysis, CRISPR-Cas Systems
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