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Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies

ABSTRACT: Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies

PROVIDER: PRJNA858842 | ENA |

REPOSITORIES: ENA

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Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies [ChIP-seq]

Project description:Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies [ChIP-seq]

| PRJNA858845 | ENA

Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies [RNA-seq]

Project description:Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies [RNA-seq]

| PRJNA858065 | ENA

Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies [RNA-seq]

Project description:To investigate the role of KDM6B in the pathogenesis of truncated ASXL1-mediated myeloid malignancies, we purified the Lin-cKit+ cells from bone marrow of WT, Kdm6bΔ/+, Asxl1Y588XTg, and Asxl1Y588XTg;Kdm6bΔ/+ mice and performed the bulk RNA-seq to study the dysregulated genes due to the reduction of Kdm6b in Asxl1 mutant context.

2025-07-12 | GSE208054 | GEO

Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies [ChIP-seq]

Project description:To investigate the role of KDM6B in the pathogenesis of truncated ASXL1-mediated myeloid malignancies, we purified the Lin-cKit+ cells from bone marrow of WT, Kdm6bΔ/+, Asxl1Y588XTg, and Asxl1Y588XTg;Kdm6bΔ/+ mice and performed ChIP-seq using H3K27me3 to investigate the gene regulation by this specific histone modification.

2025-07-12 | GSE208246 | GEO

Inhibition of lysine demethylase 6B blocks the development of ASXL1 truncation-mediated myeloid malignancies

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

2025-07-12 | GSE208249 | GEO

Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.

Project description:ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.

| S-EPMC10760961 | biostudies-literature

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

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

Human herpesvirus 6B (HHV-6B) detection and genome-wide host expression profiles implicate HHV-6B as a pulmonary pathogen after hematopoietic cell transplantation

Project description:Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplantation (HCT). We conducted a prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT. We tested blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and performed RNA-seq on paired blood. Among 116 participants, HHV-6B DNA was detected in 37% of BALs, 49% of which had HHV-6B mRNA detection. We established an HHV-6B DNA threshold (≥2.3 log10copies/ml in BALF) that was highly predictive of HHV-6B mRNA detection and increased risk for death from respiratory failure (adjusted HR, 2.35; 95% CI, 1.08-5.11). Participants with HHV-6B DNA in BALF exhibited distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.

2023-12-18 | GSE244210 | GEO

ASXL1 Mutations Promote Myeloid Transformation Through Loss of PRC2-Mediated Gene Repression

Project description:Recurrent somatic ASXL1 mutations occur in patients with myelodysplasia (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML), and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here we identify that ASXL1 mutations result in loss of PRC2-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data we identify targets of ASXL1 repression including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the Polycomb repressive complex 2 (PRC2), and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. To assess the genome-wide effects of ASXL1 loss on chromatin state we performed chromatin immunoprecipitation followed by next generation sequencing (CHIP-seq) for histone modifications known to be associated with PcG (histone H3 lysine 27 trimethylation (H3K27me3)) or TxG activity (histone H3 lysine 4 trimethylation (H3K4me3)) in UKE1 cells expressing empty vector (EV) or 2 independent validated shRNAs for ASXL1. This Series represents the ChIP-Seq data (not the microarray data referenced in the summary above). The related micorarray data are available in GEO as GSE38692.

2012-08-21 | E-GEOD-38861 | biostudies-arrayexpress

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