Screening of ETO2-GLIS2-induced Super Enhancers identifies targetable cooperative dependencies in acute megakaryoblastic leukemia.
Salima BenbarcheCécile K LopezEralda SalatajZakia AidCécile ThirantMarie-Charlotte LaiguillonSéverine LecourtYannis BelloucifCamille VaganayMarion AntoniniJiang HuAlexandra da Silva BabinetDelphine Ndiaye-LobryBryann PardieuArnaud PetitAlexandre PuissantJulie ChaumeilThomas MercherCamille LobryPublished in: Science advances (2022)
Super Enhancers (SEs) are clusters of regulatory elements associated with cell identity and disease. However, whether these elements are induced by oncogenes and can regulate gene modules cooperating for cancer cell transformation or maintenance remains elusive. To address this question, we conducted a genome-wide CRISPRi-based screening of SEs in ETO2-GLIS2 + acute megakaryoblastic leukemia. This approach revealed SEs essential for leukemic cell growth and survival that are induced by ETO2-GLIS2 expression. In particular, we identified a de novo SE specific of this leukemia subtype and regulating expression of tyrosine kinase-associated receptors KIT and PDGFRA . Combined expression of these two receptors was required for leukemic cell growth, and CRISPRi-mediated inhibition of this SE or treatment with tyrosine kinase inhibitors impaired progression of leukemia in vivo in patient-derived xenografts experiments. Our results show that fusion oncogenes, such as ETO2-GLIS2, can induce activation of SEs regulating essential gene modules synergizing for leukemia progression.
Keyphrases
- acute myeloid leukemia
- genome wide
- poor prognosis
- tyrosine kinase
- bone marrow
- liver failure
- dna methylation
- drug induced
- single cell
- copy number
- epidermal growth factor receptor
- binding protein
- stem cells
- gene expression
- mesenchymal stem cells
- cell therapy
- aortic dissection
- long non coding rna
- network analysis
- replacement therapy