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SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression

ABSTRACT: SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression

PROVIDER: PRJNA515883 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5956290_1.fastq.gz	Fastqsanger.gz
	SRR5956290_2.fastq.gz	Fastqsanger.gz
	SRR5956300_1.fastq.gz	Fastqsanger.gz
	SRR5956300_2.fastq.gz	Fastqsanger.gz
	SRR5956310.fastq.gz	Fastqsanger.gz

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SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression [sequencing]

Project description:Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality necessitating further improvements in diagnosis and therapy. Targeted therapies directed against epigenetic regulators, which are frequently mutated or misregulated in acute leukemia, are emerging as candidate approaches in preclinical studies and early trials. However, the epigenetic factors involved in most ALLs are not well defined or functionally characterized. In this study, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is over-expressed in a wide spectrum of leukemias, required for their maintenance in vitro and in vivo, and its elevated expression correlates with a poor prognosis in clinical cohorts. In a subset of ALL with the preBCR+ phenotype, SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1. In this subset, SETDB2 epigenetically suppresses expression of the cell cycle inhibitor CDKN2C through histone H3K9 tri-methylation thus establishing a novel oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. In addition to targeting SETDB2 alone, its knockdown significantly enhanced sensitivity to kinase and epigenetic inhibitors suggesting a potential approach to future combination treatments. Our studies define an epigenetic role for SETDB2 in leukemia pathogenesis, and provide a mechanistic rationale for targeting SETDB2 therapeutically in a subset of leukemia.

2018-05-30 | GSE102947 | GEO

SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.

Project description:Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL.

| S-EPMC5963704 | biostudies-literature

Microarray data of mouse primary E2A-PBX1 leukemia and preleukemia cells

Project description:Microarray data of mouse primary E2A-PBX1 leukemias and preleukemia cells were compared to wild-type B-cell progenitor cells Aberrant activation of signaling pathways has been linked to leukemogenesis, however, little is known about cell signaling perturbations induced by fusion transcription factors. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the chimeric fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) ALL. We describe here signaling network remodeling by E2A-PBX1 in pre-B-ALL, which results in hyperactivation of PLCγ2. Depletion of PLCγ2 reduced proliferation of mouse and human ALLs, including E2A-PBX1 leukemias, and increased disease-free survival after secondary transplantation. E2A-PBX1 binds and activates the transcription of its target genes ZAP70, SYK and LCK, which encode kinases upstream of PLCγ2. Efficient shRNA-mediated depletion of the respective upstream kinases decreased cell proliferation and phosphorylated levels of PLCγ2 (pPLCγ2). Pairwise compound knockdown of ZAP70, SYK or LCK showed additive effects on cell growth inhibition, providing a rationale for combination therapy. Inhibition of SYK, LCK and SFK with small molecule inhibitors, including dasatinib, was highly effective in reducing pPLCγ2 and inhibiting proliferation of preBCR+ leukemias in vitro and in vivo. Combination small molecule inhibition of SYK, LCK and SFK showed promising preclinical efficacy for preBCR+/E2A-PBX1+ leukemias. These studies demonstrate that E2A-PBX1 induces signaling pathway perturbations upstream of PLCγ2, which render leukemias amenable to targeted therapeutic inhibition.

2016-05-03 | GSE81010 | GEO

Chromatin Immunoprecipitation of E2A-PBX1 in the cell line 697

Project description:Data from "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels The experiment showed direct targets of the fusion protein. In the manuscript, individual gene targets are explained, along with DNA motifs that the fusion protein bound to. Demonstrates the "direct" targets of the E2A-PBX1 leukemia fusion protein, which is a feature of about 5% of all chilldhood leukemia. Comparison of the ChIP pull-down from E2A antibody in an E2A-PBX1 positive cell line, compared to the input DNA. There are 3 replicate experiments

2013-11-23 | E-GEOD-52653 | biostudies-arrayexpress

Chromatin Immunoprecipitation of E2A-PBX1 in the cell line 697

2013-11-23 | GSE52653 | GEO

Homo sapiens

Project description:SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression [sequencing]

| PRJNA399516 | ENA

BCL6 represents a therapeutic target in E2A-PBX1 and MLL-rearranged acute lymphoblastic leukemia

Project description:We used ChIPseq to identify target genes of BCL6 that are involved in leukemogenesis of E2A-PBX1 and MLL-AF4 pre-B ALL.

2019-12-31 | GSE59541 | GEO

SETDB2 links E2A-PBX1 to cell cycle dysregulation in acute leukemia through CDKN2C repression

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

2019-01-19 | GSE125334 | GEO

Global gene expression profile of CNS-infiltrating E2A-PBX1+/preBCR+ ALL cells

Project description:In order to elucidate mechanism of resistance to BTKi and dasatinib in CNS-infiltrating leukemia cells and to investigate the CNS homing of E2A-PBX1/preBCR+ ALL cells, we performed global transcriptome analysis by RNA sequencing. RNA was isolated from CNS-infiltrating cells from vehicle, dasatinib, ibrutinib, dasatinib + ibrutinib-treated mice

2024-03-15 | GSE221238 | GEO

SNP arrays to detect copy number changes in t(1;19) E2A-PBX1 positive leukemias

Project description:The experiment was to detect the identity and range of copy number alterations in a subtype of childhood leukemia defined by t(1;19) translocaitons The data will be presented in the manuscript "Direct and indirect targets of the E2A-PBX1 leukemia-specific fusion protein" to be published in PLOS One, authors Christofer Diakos, Yuanyuan Xiao, Shichun Zheng, Leo Kager, Michael Dworzak, Joseph L. Wiemels

2013-11-23 | GSE52654 | GEO

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