Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis [II]

Clonal hematopoiesis (CH) results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. Here, 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 CH-associated genes, like 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. Overall design: To analyze the effect of germline runx1 homozygous mutant hematopoiesis compared to runx1 heterozygous hematopoiesis. Embryos from runx1 heterozygous incross were grown to adulthood. Whole kidney marrow cells from 4 runx1 heterozygous and 4 runx1 homozygous mutant zebrafish were collected for preparation for 10x single cell RNA sequencing.