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Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, clonal fitness, and structure

ABSTRACT: Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, clonal fitness, and structure

PROVIDER: PRJNA1219176 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32229000_1.fastq.gz	Fastqsanger.gz
	SRR32229000_2.fastq.gz	Fastqsanger.gz
	SRR32229100_1.fastq.gz	Fastqsanger.gz
	SRR32229100_2.fastq.gz	Fastqsanger.gz
	SRR32229001_1.fastq.gz	Fastqsanger.gz

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Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, clonal fitness, and structure

Project description:Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713). We demonstrate pathway-specific fitness advantage and clonal composition significantly influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MAC120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.

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

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Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

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Project description:Clonal hematopoiesis resulting from enhanced fitness of mutant hematopoietic stem cells (HSCs) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of DNMT3AR882/+ clonal hematopoiesis (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs as well as stimulated mutant B lymphoid cell production. Genetic loss of TNFα receptor TNFR1 impaired mutant HSC fitness without altering lineage output, while loss of TNFR2 reduced lymphoid cell production and favored myeloid cell production from mutant HSCs without altering overall fitness. These results support a model where clone size and mature blood lineage production can be independently controlled to harness potential beneficial aspects of clonal hematopoiesis.

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

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

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Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure.

Project description:Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.

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