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Gene expression profiles of mutant ASXL1 knock-in HSPCs

ABSTRACT: Gene expression profiles of mutant ASXL1 knock-in HSPCs

PROVIDER: PRJNA743508 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15034245_1.fastq.gz	Fastqsanger.gz
	SRR15034245_2.fastq.gz	Fastqsanger.gz
	SRR15034246_1.fastq.gz	Fastqsanger.gz
	SRR15034246_2.fastq.gz	Fastqsanger.gz
	SRR15034247_1.fastq.gz	Fastqsanger.gz

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Gene expression profiles of mutant ASXL1 knock-in HSPCs

Project description:To assess the effect of mutant ASXL1 (ASXL1-MT) on gene expression and RNA splicing in hematopoietic cells, we performed RNA-seq using HSPCs (bone marrow lineage-, c-Kit+ cells) derived from control or ASXL1-MT-KI mice.

2021-07-05 | GSE179375 | GEO

Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

Project description:Additional Sex Combs Like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. Here we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphologic dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. ChIP-seq analysis demonstrated opposing effects of wildtype and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.

2018-02-28 | GSE111067 | GEO

Asxl1 and Cebpa cooperation in AML revealed by a novel Asxl1 mutant mouse model

Project description:Asxl1 is one of the most commonly mutated genes in malignancies including myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML). We generated a mouse model that harbors the most common mutation on ASXL1 gene detected in MDS patients: c.1934dupG, p.G646WfsX12 at the endogenous murine Asxl1 locus: the G643WfsX12 mutant, from here on referred as Asxl1G643W. Mutations on Asxl1 co-occur with mutations on CEBPA in AML patients, therefore, in order to understand how Asxl1 and Cebpa co-operate, we set up to cross our Cebpa-p30 mutant mouse model with our newly generated Asxl1 G643Wfs12 mutant. In this study we provided mechanistic information about the cooperation between these two factors. Furthermore, our mouse model proved able to recapitulate the chemotherapy response of human patients with Asxl1 mutations, thus representing a potent tool for future preclinical studies focusing on Asxl1 mutant AML.

2020-05-12 | GSE133314 | GEO

Epigenome of ASXL1-mutant and ASXL1-wildtype chronic myelomonocytic leukemia

Project description:Epigenome of ASXL1-mutant and ASXL1-wildtype chronic myelomonocytic leukemia

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Transcriptome of ASXL1-mutant and ASXL1-wildtype chronic myelomonocytic leukemia

Project description:Transcriptome of ASXL1-mutant and ASXL1-wildtype chronic myelomonocytic leukemia

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The effects of expression of mutant ASXL1 and HHEX on hematopoietic cells

Project description:To identify target genes of mutant ASXL1 (ASXL1-MT) and HHEX in hematopoietic cells, we performed RNA-seq using RUNX1-ETO expressing cord blood cells transduced with vector or ASXL1-MT together with vector or HHEX.

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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.

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Project description:To identify target genes of mutant ASXL1 and BAP1 in hematopoietic cells, we performed RNA-seq using murine c-kit positive cells transduced with ASXL1-MT (MT) or ASXL1-MT-K351R (KR) together with vector or BAP1. Method：Murine c-kit positive bone marrow cells were transduced with ASXL1-MT (MT) or ASXL1-MT-K351R (KR) (coexpressing blastcidin resistant gene) together with vector or BAP1 (coexpressing puromycin resistant gene). After the selection with blasticidin and puromycin for three days, colony-forming cells were collected to extract RNA for RNA-seq analysis.

2018-05-25 | GSE114861 | GEO

RNA sequencing of zebrafish asxl1+/+ and asxl1-/-

Project description:ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. In patients, ASXL1 mutations are usually heterozygous frameshift or non-sense mutations leading to C-terminal truncation. Here, we generated an endogenous C-terminal truncated Asxl1 mutant in zebrafish which is more comparable to human malignant leukemia patients. Our data showed that at embryonic stage, neutrophil differentiation was explicitly blocked in our mutant. To understand the basis for the impairment of neutrophil differentiation in zebrafish asxl1 mutants, we performed RNA-seq of asxl1 mutants at 3dpf and their littermate controls. Similar with the phenotype we observed, the expression of neutrophil markers were all included in down-regulated genes. Nonetheless, the expression of myeloid progenitor marker and macrophage marker were not impaired in asxl1 mutants. We also found inflammatory cytokine and matrix metalloproteinases were upregulated after mutated asxl1. It suggests that neutrophil deficiency may stimulate the expression of some inflammatory cytokines and enhances the inflammatory responds. Therefore, transcriptome analysis mainly represented the disruption of neutrophil development.

2021-08-04 | GSE142214 | GEO

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