RESUMEN

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 hematopoiesis­associated 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.

Asunto(s)

Hematopoyesis Clonal , Células Madre Hematopoyéticas/fisiología , Inflamación , Células Mieloides/fisiología , Animales , Sistemas CRISPR-Cas , Citocinas/genética , Citocinas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Mutación del Sistema de Lectura , Genes p53 , Inflamación/genética , Mutación , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , RNA-Seq , Proteínas Represoras/genética , Selección Genética , Análisis de la Célula Individual , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética