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Effect of PROTAC-mediated BRD4 degradation in acute myeloid leukemia [OCI-AML3]

ABSTRACT: BRD4, a member of the BET family of histone readers, binds to acetylated lysine of histone H3 and promotes assembly of super-enhancer complexes that drive expression of key oncogenes in acute myeloid leukemia (AML) and other cancers. ARV-825 is a proteolysis-targeting chimera (PROTAC) that targets BRD4 for CRBN-mediated ubiquitination and degradation. We treated the AML cell line OCI-AML3, as well as primary tumor cells from a case of AML, with ARV-825 in vitro. At low concentrations, ARV-825 caused profound and sustained reduction in BRD4 protein levels. This caused reduction in transcription of key genes including MYC, anti-apoptotic BCL2 and BCLXL, PIM1, and CD44. Downstream effects included loss of CXCR4 surface expression and mitochondrial respiration; increased reactive oxygen species; toxicity to AML cells in vitro; and efficacy vs. OCI-AML3 cells in a mouse model of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101380 | GEO | 2019/10/01

REPOSITORIES: GEO

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