Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

• Published in: Science (American Association for the Advancement of Science) Vol. 374; no. 6568; pp. 768 - 772
• Main Authors: Avagyan, S, Henninger, J E, Mannherz, W P, Mistry, M, Yoon, J, Yang, S, Weber, M C, Moore, J L, Zon, L I
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 05.11.2021
• Subjects: Animals; Autosomal dominant inheritance; Blood; Clonal Hematopoiesis; Cloning; CRISPR-Cas Systems; Cytokines - genetics; Cytokines - metabolism; DNA (Cytosine-5-)-Methyltransferases - genetics; Dominance; Fitness; Frameshift Mutation; Gene expression; Genes; Genes, p53; Hematological diseases; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - physiology; Immunomodulation; Immunomodulators; Inflammation; Inflammation - genetics; Mutagenesis; Mutants; Mutation; Myeloid cells; Myeloid Cells - physiology; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Progenitor cells; Progeny; Repressor Proteins - genetics; Reproductive fitness; RNA-Seq; Selection, Genetic; Single-Cell Analysis; Stem cells; Transcription; Zebrafish; Zebrafish - embryology; Zebrafish - genetics; Zebrafish Proteins - genetics
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aba9304

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 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, , abrogated the ability of 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.