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Series GSE195497 Query DataSets for GSE195497
Status Public on Oct 11, 2022
Title EVI1 drives leukemogenesis through aberrant activation of ERG
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary Chromosomal rearrangements involving EVI1 (MECOM) define a subtype of acute myeloid leukemia (AML) that is associated with a two-year survival rate of <10%. Gene regulatory functions of EVI1 are largely elusive and no targeted therapeutics exist. We developed experimentally tractable murine and human leukemia models that recapitulate phenotypic and transcriptional features of EVI1-rearranged AML and enable large-scale loss-of-function screens. We characterize EVI1-controlled transcriptional programs in cell culture and in vivo, perform CRISPR screens and identify the ETS-related transcription factor ERG as the only gene that is specifically required for EVI1-driven AML. ERG is transcriptionally activated by EVI1 and overexpressed in EVI1-rearranged AML patients. ERG suppression selectively induces terminal differentiation of leukemia cells. EVI1 becomes dispensable for leukemia cells upon ectopic expression of ERG, indicating that key functions of EVI1 are mediated through aberrant activation of ERG. Interfering with this regulatory axis may therefore provide new entry points for rational therapies.
 
Overall design RNA-seq of leukemia cells derived from mouse models driven by DOX-regulatable or constitutive RUNX1/EVI1, and NRAS(G12D) upon DOX treatment of mice (31848-31861). Quant-seq of in-vitro-cultured murine leukemia cells driven by constitutive RUNX1/EVI1 and NRAS(G12D) upon knockdown of RUNX1/EVI1 compared to ctrl (160665-160670). Quant-seq of in-vitro-cultured human AML cells (HNT-34) driven by EVI1 upon knockdown of EVI1 compared to ctrl (61648-61653). Quant-seq of in-vitro-cultured murine leukemia cells driven by constitutive RUNX1/EVI1, NRAS(G12D) upon knockdown of EVI1 in the presence or absence of ectopic ERG expression (160677-160688). ATAC-seq of murine leukemia cells driven by RUNX1/EVI1, NRAS(G12D) upon knockdown of RUNX1/EVI1 compared to ctrl (162167, 162169)
 
Contributor(s) Schmoellerl J, Barbosa IA, Minnich M, Andersch F, Smeenk L, Havermans M, Eder T, Neumann T, Jude J, Fellner M, Ebert A, Steininger M, Delwel R, Grebien F, Zuber J
Citation(s) 36095844
Submission date Jan 26, 2022
Last update date Oct 19, 2022
Contact name Florian Andersch
E-mail(s) florian.andersch@imp.ac.at
Organization name Institute of Molecular Pathology
Lab Johannes Zuber
Street address Campus-Vienna-Biocenter 1
City Vienna
ZIP/Postal code 1030
Country Austria
 
Platforms (4)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (38)
GSM5839427 DOX ctrl mouse model - OFF DOX - Replicate 1
GSM5839428 DOX ctrl mouse model - OFF DOX - Replicate 2
GSM5839429 DOX ctrl mouse model - OFF DOX - Replicate 3
Relations
BioProject PRJNA800809

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Supplementary file Size Download File type/resource
GSE195497_RAW.tar 130.0 Mb (http)(custom) TAR (of BIGWIG)
GSE195497_normalized-expression-HNT34-samples.txt.gz 521.1 Kb (ftp)(http) TXT
GSE195497_normalized-expression-murine-samples.txt.gz 3.1 Mb (ftp)(http) TXT
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