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EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212979 | GEO | 2023/10/04

REPOSITORIES: GEO

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EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors.

Project description:EWS fusion oncoproteins underlie the pathogenesis of several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive mesenchymal tumor driven by fusions between the disordered domain of EWS and the developmental transcription factor WT1. Here we combined chromatin occupancy and long-range interaction profiles to identify EWS-WT1-dependent gene regulation networks and directly controlled target genes. We show that EWS-WT1 operates primarily as a powerful activator of distal regulatory elements and controls an oncogenic gene expression program that characterize primary DSRCTs. Moreover, EWS-WT1 has two isoforms that differ by three amino acids in their DNA binding domain (+/- KTS), as observed for wild type WT1, and we show that each fusion isoform has a specific DNA binding profile that is distinct from its wild type counterparts and requires a functional EWSR1 prion like domain. Remarkably, xenograft experiments using human mesothelial cells, candidate cells of origin of DSRCT, reveal that both isoforms are required to generate viable tumors that resemble DSRCT. Finally, we identify new candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex isoform-dependent oncogenic activity of EWS-WT1.

2024-10-01 | GSE248842 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [HiChIP]

2023-10-04 | GSE212978 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [ChIP-seq]

2023-10-04 | GSE212977 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [RNA-seq]

2023-10-04 | GSE212976 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [Hi-C]

2023-10-04 | GSE242863 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors

Project description:EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors

| PRJNA1125509 | ENA

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors

Project description:EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors

| PRJNA878554 | ENA

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors.

Project description:EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors.

| PRJNA1046095 | ENA

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [HiChIP]

Project description:EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [HiChIP]

| PRJNA878594 | ENA

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [Hi-C]

Project description:EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [Hi-C]

| PRJNA1015192 | ENA

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