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KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

ABSTRACT: KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

PROVIDER: PRJNA885884 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21772652_1.fastq.gz	Fastqsanger.gz
	SRR21772652_2.fastq.gz	Fastqsanger.gz
	SRR21772653_1.fastq.gz	Fastqsanger.gz
	SRR21772653_2.fastq.gz	Fastqsanger.gz
	SRR21772654_1.fastq.gz	Fastqsanger.gz

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KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress [Human RNAseq]

Project description:KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress [Human RNAseq]

| PRJNA885887 | ENA

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress [Mouse RNAseq]

Project description:KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress [Mouse RNAseq]

| PRJNA885888 | ENA

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress [Mouse RNAseq]

Project description:Kdm6b mutant cells are at a survival disadvantage in NOTCH1- induced T-ALL

2022-10-01 | GSE214575 | GEO

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress [Human RNAseq]

Project description:Kdm6b mutant cells are at a survival disadvantage in NOTCH1- induced T-ALL

2022-10-01 | GSE214573 | GEO

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress.

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.

| S-EPMC10081958 | biostudies-literature

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

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

2022-10-01 | GSE214576 | GEO

Expression data from Sh2b3 Knock-out NOTCH1-induced leukemias

Project description:To formally address the tumor suppressor activity of Sh2b3 in vivo, we tested the interaction between oncogenic NOTCH1 and Sh2b3 loss in a retroviral- transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Sh2b3 wild type and Sh2b3–/– NOTCH1 induced leukemias

2013-11-06 | E-GEOD-44025 | biostudies-arrayexpress

Expression data from Hes1 conditional knock-out NOTCH1-induced leukemias

Project description:To formally address the biological activity of Hes1 in vivo, we tested the interaction between oncogenic NOTCH1 and acute Hes1 loss in a retroviral-transduction bone marrow transplantation model of NOTCH-induced T-ALL Forced expression of activated NOTCH1 in this model typically results in full leukemia transformation 5-10 weeks later. We performed microarray gene expression analysis of Hes1 wild type and Hes1-/- NOTCH1 induced leukemias

2015-05-07 | E-GEOD-65863 | biostudies-arrayexpress

Kdm6b is Required for Self-Renewal of Normal and Leukemic Stem Cells Under Proliferative Stress

Project description:Recent studies have indicated that the histone 3 lysine 27 (H3K27me2/3) demethylase KDM6B (JMJD3) is frequently upregulated in a myriad of blood disorders including myelodysplastic syndrome (MDS), T-cell acute lymphoblastic leukemia (T-ALL), and multiple myeloma (MM) suggesting it may have important functions in the pathogenesis of hematopoietic cancers. Here, we sought to determine the role of Kdm6b in hematopoietic stem cell (HSC) fate decisions under normal and malignant conditions to evaluate its potential as a therapeutic target. We show that loss of Kdm6b leads to a significant reduction in phenotypic and functional HSCs in adult mice, and that Kdm6b is necessary for HSC self-renewal in response to inflammatory, genotoxic and oncogenic stress. Additionally, we show that loss of Kdm6b in HSCs leads to a stress-response gene expression signature in native HSCs that is independent of its demethylase activity. Loss of Kdm6b lead to increased expression of a subset of genes implicated in HSC quiescence (e.g. Fos, Jun, Ier2, Dusp1, Zfp36). Upon inflammatory or replicative stress, HSCs deficient for Kdm6b are not able to efficiently resolve this gene expression program, leading to increased quiescence and a self-renewal block, forcing them to differentiate. These findings show that Kdm6b is necessary for self-renewal of normal and leukemic stem cells, and suggest inhibiting Kdm6b in blood cancers in the presence of proliferative agents may force differentiation and eventual depletion of leukemic stem cells.

2019-07-17 | GSE110378 | GEO

Expression data from Sh2b3 Knock-out NOTCH1-induced leukemias

2013-11-06 | GSE44025 | GEO