CUT&RUN Profiling in CBF-Glis2 AMLs Identifies the Chromatin Remodeler Brg1 as a Key Dependency
Ontology highlight
ABSTRACT: Oncogenic fusions involving transcription factors are present in the majority of pediatric leukemias, however, the context-specific mechanisms they employ to drive cancer remain poorly understood. CBFA2T3-GLIS2 (C/G) fusions occur in treatment-refractory acute myeloid leukemias and are restricted to young children. To understand how the C/G fusion drives oncogenesis we applied CUT&RUN chromatin profiling to an umbilical cord blood/endothelial cell (EC) co-culture model of C/G AML that recapitulates the biology of this malignancy. We find C/G fusion binding is mediated by its zinc finger domains. Integration of fusion binding sites in C/G-transduced cells with PRC2 sites in control cord blood cells identifies MYCN, WT1, and GATA2 as C/G targets. Transcriptomic analysis of a pediatric AML cohort shows that these genes are upregulated in C/G patient samples. Single cell RNA-sequencing of umbilical cord blood identifies a population of megakaryocyte precursors that already express many of these genes despite lacking the fusion. By integrating CUT&RUN data with CRISPR dependency screens we identify BRG1/SMARCA4 as a vulnerability in C/G AML. Brg1 profiling in C/G patient-derived cell lines shows that the CBFA2T3 promoter is a binding site, and treatment with clinically-available Brg1 inhibitors reduces fusion levels and downstream C/G targets including N-Myc, killing C/G leukemia cells.
ORGANISM(S): Homo sapiens
PROVIDER: GSE239849 | GEO | 2023/08/07
REPOSITORIES: GEO
ACCESS DATA