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Distinct TNF Receptors Dictate Stem Cell Fitness Versus Lineage Output in Clonal Hematopoiesis of Aging

ABSTRACT: Distinct TNF Receptors Dictate Stem Cell Fitness Versus Lineage Output in Clonal Hematopoiesis of Aging

PROVIDER: PRJNA782903 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17016941.fastq.gz	Fastqsanger.gz
	SRR17016942.fastq.gz	Fastqsanger.gz
	SRR17016943.fastq.gz	Fastqsanger.gz
	SRR17016944.fastq.gz	Fastqsanger.gz
	SRR17016945.fastq.gz	Fastqsanger.gz

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Distinct TNF Receptors Dictate Stem Cell Fitness Versus Lineage Output in Clonal Hematopoiesis of Aging

Project description:Clonal hematopoiesis of aging results from enhanced fitness of mutant hematopoietic stem cells (HSCs) and associates with both favorable and unfavorable health outcomes related to lineage cell types produced by mutant HSCs. The extent to which lineage output can be controlled in clonal hematopoiesis is unknown. Using a mouse model of DNMT3AR882/+ clonal hematopoiesis (Dnmt3aR878H/+), we find that aging-induced TNFα signaling drives selective advantage of mutant HSCs concomitant with B lymphoid lineage production. Genetic loss of TNFα receptor TNFR1 impaired mutant HSC fitness while loss of TNFR2 abrogated lymphoid production and resulted in unrestrained myeloid cell production from mutant HSCs. These results support a model where clone size and lineage output can be independently targeted to harness potential beneficial aspects of clonal hematopoiesis.

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Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

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

Project description: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.

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