The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

<jats:title>Abstract</jats:title><jats:p>Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of <jats:italic>EVI1</jats:italic> is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a <jats:italic>MYC</jats:italic> super-enhancer (<jats:italic>MYC</jats:italic> SE) to the <jats:italic>EVI1</jats:italic> locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of <jats:italic>EVI1</jats:italic> by the hijacked <jats:italic>MYC</jats:italic> SE. This <jats:italic>MYC</jats:italic> SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for <jats:italic>EVI1</jats:italic> overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the <jats:italic>MYC</jats:italic> SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the <jats:italic>EVI1</jats:italic> promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which <jats:italic>EVI1</jats:italic> uses this docking site to hijack enhancers active in early hematopoiesis.</jats:p>