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Primary and acquired drug resistance imposes a major threat to achieving optimized clinical outcomes during cancer treatment. Aberrant changes in epigenetic modifications are closely involved in drug resistance of tumor cells. 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 the CRISPR interference technology, we identified the second intron of IncRNA,  PVT1 , as a unique bona fide gained enhancer that restored  MYC  transcription independent of BRD4 recruitment in leukemia. A combined BETi and CDK7 inhibitor treatment abolished  MYC  transcription by impeding RNAPII loading without affecting  PVT1 -mediated chromatin looping at the  MYC  locus in BETi-resistant leukemia cells. Together, our findings have established the feasibility of targeting enhancer plasticity to overcome drug resistance associated with epigenetic therapies.

A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells