PUBLICATION
Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis
- Authors
- Avagyan, S., Henninger, J.E., Mannherz, W.P., Mistry, M., Yoon, J., Yang, S., Weber, M.C., Moore, J.L., Zon, L.I.
- ID
- ZDB-PUB-211116-2
- Date
- 2021
- Source
- Science (New York, N.Y.) 374: 768-772 (Journal)
- Registered Authors
- Zon, Leonard I.
- Keywords
- none
- Datasets
- GEO:GSE176037, GEO:GSE176036, GEO:GSE150373
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems
- Clonal Hematopoiesis*
- Cytokines/genetics
- Cytokines/metabolism
- DNA (Cytosine-5-)-Methyltransferases/genetics
- Frameshift Mutation
- Genes, p53
- Hematopoietic Stem Cells/physiology*
- Inflammation*/genetics
- Mutation
- Myeloid Cells/physiology*
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- RNA-Seq
- Repressor Proteins/genetics
- Selection, Genetic
- Single-Cell Analysis
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- PubMed
- 34735227 Full text @ Science
Citation
Avagyan, S., Henninger, J.E., Mannherz, W.P., Mistry, M., Yoon, J., Yang, S., Weber, M.C., Moore, J.L., Zon, L.I. (2021) Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis. Science (New York, N.Y.). 374:768-772.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping