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

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

PROVIDER: PRJNA734619 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14713033.fastq.gz	Fastqsanger.gz
	SRR14713034.fastq.gz	Fastqsanger.gz
	SRR14713035.fastq.gz	Fastqsanger.gz
	SRR14713036.fastq.gz	Fastqsanger.gz
	SRR14713037.fastq.gz	Fastqsanger.gz

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Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

Project description:Resistance to inflammation underlies enhanced fitness in 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]

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.

2021-12-02 | GSE176036 | GEO

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

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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.

2021-11-25 | GSE189406 | GEO

Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output in Murine Dnmt3a-Mutant Clonal Hematopoiesis

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.

2022-05-25 | GSE203550 | GEO

Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-12-02 | GSE176037 | GEO

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

Project description:Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We used a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2- mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models the human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

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

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Identifying non-genetic determinants of malignant clonal fitness at single cell resolution (clonal competition scRNAseq)

Project description:All cancers emerge following a period of clonal selection and subsequent clonal expansion. Whilst the evolutionary principles imparted by genetic intra-tumour heterogeneity (ITH) are becoming increasingly clear, little is known about the non-genetic mechanisms that contribute to ITH and malignant clonal fitness. Using SPLINTR, a synthetic expressed barcoding strategy, in three clinically relevant mouse models of acute myeloid leukaemia (AML) we find that malignant clonal dominance is a stable and heritable property that is facilitated by the repression of antigen presentation and the increased expression of Slpi, a leukocyte protease inhibitor that has not previously been characterised in AML. Increased transcriptional heterogeneity is a consistent feature enabling clonal fitness in diverse tissue / immune microenvironments and in the context of clonal competition between genetically distinct clones within a uniform microenvironment. Compared to extramedullary sites, leukaemia initiating capacity is most enriched in malignant cells resident within the bone marrow microenvironment and leukaemia stem cells (LSC), like normal haematopoietic stem cells, display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. Finally, we demonstrate that clonal output does not dictate sensitivity to chemotherapy and both high and low output LSC clones retain marked cellular plasticity enabling them to survive potent therapeutic challenge and persist as minimal residual disease. Together these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness which may inform future therapeutic strategies.

2021-11-08 | GSE161673 | GEO

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