Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788288 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17209133_1.fastq.gz | Fastqsanger.gz | |||
| SRR17209133_2.fastq.gz | Fastqsanger.gz | |||
| SRR17209134_1.fastq.gz | Fastqsanger.gz | |||
| SRR17209134_2.fastq.gz | Fastqsanger.gz | |||
| SRR17209135_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 70 |
Similar Datasets
Project description:Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis in myeloid malignancies and are also found in pre-malignant clonal hematopoiesis of indeterminate potential (CHIP). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved and therapeutic targeting has remained elusive. Here, we demonstrate that ASXL1 mutations are frequently founding lesions in acute myeloid leukemia (AML) and lead to the expression of a functional, truncated protein. We developed a human disease model that faithfully recapitulates ASXL1-mutant CHIP with increased self-renewal and in vivo competitive advantage that can spontaneously progress to a lethal myeloid malignancy. We determined that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased chromatin accessibility, and activation of both myeloid and stem cell gene expression programs. Finally, we identified dysregulation of H2AK119Ub as a therapeutic vulnerability and demonstrated that ASXL1-mutant cells are vulnerable to inhibition of the PRC1 complex.
2024-02-07 | GSE190738 | GEO
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
Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex. ChIP-Seq for H2AK119Ub, H3K4me3, H3K27me3 on EML cells. RNA-Seq on EML cells expressing ASXL1(1-479)+BAP1 and control.
2015-03-11 | E-GEOD-65555 | biostudies-arrayexpress
Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
2021-02-08 | MSV000086816 | MassIVE
Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex.
2015-03-11 | GSE65555 | GEO
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
Project description:The ASXL1 gene is the human homolog of the Drosophila Asx gene, a core subunit in the BAP1 histone H2A deubiquitinase complex. Mutations of ASXL1 occur in multiple myeloid neoplasms and are uniformly associated with poor prognosis. However, the molecular mechanism through which ASXL1 mutations alter BAP1 activity to drive leukemogenesis remains unclear. Here we demonstrate that cancer-associated frame-shift ASXL1 mutations, which were originally proposed to act as destabilizing loss-of-function mutations, in fact encode truncated stable gain-of-function proteins. Truncated ASXL1 protein stabilizes BAP1, enhances BAP1 complex recruitment to chromatin and promotes the expression of numerous leukemia associated genes. Chemical inhibition of BAP1 rescues these changes in gene expression in leukemic cells and inhibits tumor progression. This study represents a breakthrough advance in our understanding of the molecular mechanisms of ASXL1 mutations in leukemic pathogenesis and identifies small molecular inhibitors of BAP1 function as a potential targeted therapy for leukemia.
2021-03-07 | GSE166305 | GEO
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
Project description:RNA-seq and ChIP-seq data of ASXL1/2 in Hematopoiesis
| PRJNA328983 | ENA
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 | GSE279601 | GEO