Journal
SCIENCE
Volume 374, Issue 6568, Pages 768-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aba9304
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Funding
- NIH [P01HL131477, 5F31HL126338-03]
- Pedal for Pediatrics
- Alex's Lemonade Stand Foundation
- Babich Family Foundation Familial RUNX1 grant
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Research has found that mutations in clonal hematopoiesis enhance the fitness of hematopoietic stem cells, and mutations in specific genes can promote clonal dominance. Single-cell transcriptional analysis showed that these mutations stimulate the expression of inflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone.
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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