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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE208054 | GEO | 2025/07/12

REPOSITORIES: GEO

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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

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

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

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

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

| PRJNA858842 | ENA

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

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex

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

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex

2015-03-11 | GSE65555 | 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

Epigenetic targeted therapy of leukemia through a hyper-activated BAP1-ASXL1-mutant axis

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

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