PRJNA543382
A combination strategy targeting enhancer plasticity exerts synergistic legality against  BETi-resistant leukemia cells
Primary and acquired drug resistance remains problematic during cancer treatment and represents a major challenge to achieving optimized clinical outcomes. Epigenetic dysregulation emerges as a crucial component involved in drug resistance. Using BET inhibitor (BETi) resistant leukemia cells as a model system, we demonstrated herein that genome-wide enhancer remodeling played a pivotal role in driving therapeutic resistance via compensational re-expression of pro-survival genes. Capitalizing on CRISPR interference, we further identified the second intron of a IncRNA, PVT1, as a unique bona fide gained enhancer that restored MYC transcription independent of BRD4 recruitment. A combined BETi and CDK7 inhibitor treatment abolished MYC transcription by impeding RNAPII loading without affecting PVT1-mediated chromatin looping at the MYC locus. Together, our findings established the feasibility of targeting enhancer plasticity to overcome drug resistance associated with epigenetic therapies against hematological malignancies