GSE195497
EVI1 drives leukemogenesis through aberrant activation of ERG
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)