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Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1 [RNA-seq]

ABSTRACT: Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1 [RNA-seq]

PROVIDER: PRJNA973978 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24640400_1.fastq.gz	Fastqsanger.gz
	SRR24640400_2.fastq.gz	Fastqsanger.gz
	SRR24640401_1.fastq.gz	Fastqsanger.gz
	SRR24640401_2.fastq.gz	Fastqsanger.gz
	SRR24640402_1.fastq.gz	Fastqsanger.gz

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Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1 [RNA-seq]

Project description:Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during aging remain rudimentary. Here we report that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes leukemic cell expansion. Specifically, we show that ADP-D-glycero-b-D-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to gram-negative bacteria, is uniquely found in the circulation of older individuals and favors the expansion of pre-leukemic hematopoietic stem cells. Mechanistically, ADP-heptose binds its receptor, ALPK1, triggering transcriptional reprogramming that endows pre-leukemic cells with a competitive advantage. Thus, the accumulation of ADP-heptose represents a direct link between aging and expansion of rare pre-leukemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukemia and immune-related conditions.

2025-02-10 | GSE232794 | GEO

Project description:Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1

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Clonal haematopoiesis, ageing and kidney disease.

Project description:Clonal haematopoiesis of indeterminate potential (CHIP) is a preclinical condition wherein a sizeable proportion of an individual's circulating blood cells are derived from a single mutated haematopoietic stem cell. CHIP occurs frequently with ageing - more than 10% of individuals over 65 years of age are affected - and is associated with an increased risk of disease across several organ systems and premature death. Emerging evidence suggests that CHIP has a role in kidney health, including associations with predisposition to acute kidney injury, impaired recovery from acute kidney injury and kidney function decline, both in the general population and among those with chronic kidney disease. Beyond its direct effect on the kidney, CHIP elevates the susceptibility of individuals to various conditions that can detrimentally affect the kidneys, including cardiovascular disease, obesity and insulin resistance, liver disease, gout, osteoporosis and certain autoimmune diseases. Aberrant pro-inflammatory signalling, telomere attrition and epigenetic ageing are potential causal pathophysiological pathways and mediators that underlie CHIP-related disease risk. Experimental animal models have shown that inhibition of inflammatory cytokine signalling can ameliorate many of the pathological effects of CHIP, and assessment of the efficacy and safety of this class of medications for human CHIP-associated pathology is ongoing.

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Clonal Haematopoiesis-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity

Project description:Certain somatic mutations confer a fitness advantage in hematopoietic stem cells, resulting in the clonal expansion of mutant blood cells, known as clonal haematopoiesis (CH). Among the top 3 CH mutations, ASXL1 mutations present the highest risk for developing cardiovascular diseases (CVDs). However, how ASXL1 mutations induce CVDs remains totally elusive. Here we show that haematopoietic cells harbouring C-terminally truncated form of ASXL1 mutant (ASXL1-MT) accelerated development of atherosclerosis in Ldlr–/– mice. Transcriptome analyses of plaque-cells showed inflammatory signatures of monocytes and macrophages expressing ASXL1-MT. Mechanistically, wild-type ASXL1 inhibited innate immune signalling through the inhibition of IRAK1-TAK1 interaction in the cytoplasm, indicating an unexpected non-epigenetic role of ASXL1. In contrast, ASXL1-MT lost this regulatory function, leading to NF-κB activation. Intriguingly, IRAK1/4 inhibition decreased inflammatory monocytes and atherosclerosis driven by ASXL1-MT. The present work connects ASXL1 mutations with inflammation and CVDs, giving a clue to prevent CVDs in ASXL1-CH.

2024-10-25 | GSE279450 | GEO

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Project description:Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

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Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Project description:Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

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Clonal Haematopoiesis-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity [scRNA-seq]

2024-10-25 | GSE279601 | GEO

Clonal Haematopoiesis-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity

Project description:Clonal Haematopoiesis-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity

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Longitudinal dynamics of clonal haematopoiesis identifies gene-specific fitness effects

Project description:Longitudinal dynamics of clonal haematopoiesis identifies gene-specific fitness effects

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Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Project description:Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSCs. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose that modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.

2025-02-06 | GSE276989 | GEO