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:GSE150373, GEO:GSE176037, GEO:GSE176036
MeSH Terms
  • Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
  • Genes, p53
  • Frameshift Mutation
  • CRISPR-Cas Systems
  • Zebrafish Proteins/genetics
  • Single-Cell Analysis
  • Animals
  • Mutation
  • Clonal Hematopoiesis*
  • Repressor Proteins/genetics
  • Myeloid Cells/physiology*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • DNA (Cytosine-5-)-Methyltransferases/genetics
  • Inflammation*/genetics
  • RNA-Seq
  • Cytokines/genetics
  • Cytokines/metabolism
  • Hematopoietic Stem Cells/physiology*
  • Selection, Genetic
(all 21)
PubMed
34735227 Full text @ Science
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
Figures
No images available
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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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.