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.
Conflict of interest statement
The authors declare no competing interests.
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- R01HL146852/U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- RP150578/Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
- RSG-18-043-01-LIB/American Cancer Society (American Cancer Society, Inc.)
- BE-1913-20190330/Welch Foundation
- R01 HL146852/HL/NHLBI NIH HHS/United States
- RP180131/Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
- R01 HL134780/HL/NHLBI NIH HHS/United States
- R01 CA232017/CA/NCI NIH HHS/United States
- R01GM112003/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- R01HL134780/U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01CA232017/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
- RP170660/Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)
- RSG-16-215-01-TBE/American Cancer Society (American Cancer Society, Inc.)
- R01 GM112003/GM/NIGMS NIH HHS/United States