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Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens

ABSTRACT: Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers, including KMT2A-rearranged (KMT2A-r) leukemia, in preclinical studies. However, the mechanisms controlling BETi response and resistance are poorly understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-r cell lines. SPOP gene deficiency caused significant BETi resistance, which was further validated in cell line and xenograft models. In SPOP-knockout KMT2A-r leukemia cells, TRIM24 was identified as a SPOP substrate that mediates resistance to BETi. Additionally, proteomics analysis and a kinase-vulnerability CRISPR screen indicated that resistant cells are sensitive to GSK3 inhibition. Genetically perturbating TRIM24 or pharmaceutical inhibition of its downstream target GSK3 in SPOP-knockout cells reversed the BETi-resistance phenotype. A combination therapy regimen inhibiting both BET and GSK3 impeded leukemia progression in patient-derived xenografts in vivo. Our results revealed not only novel molecular mechanisms underlying BETi resistance but also a promising strategy for treating KMT2A-r leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201137 | GEO | 2023/03/30

REPOSITORIES: GEO

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