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

Nat Commun. 2020 Feb 6;11(1):740. doi: 10.1038/s41467-020-14604-6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase-Activating Kinase
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Enhancer Elements, Genetic
  • Female
  • Genes, myc / drug effects
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage
  • Humans
  • Jurkat Cells
  • K562 Cells
  • Leukemia, Experimental / drug therapy*
  • Leukemia, Experimental / genetics*
  • Leukemia, Experimental / metabolism
  • Mice
  • Models, Genetic
  • Nuclear Proteins / antagonists & inhibitors*
  • Phenylenediamines / administration & dosage
  • Pyrimidines / administration & dosage
  • RNA Polymerase II / metabolism
  • RNA, Long Noncoding / genetics
  • Transcription Factors / antagonists & inhibitors*


  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • Nuclear Proteins
  • PVT1 long-non-coding RNA, mouse
  • Phenylenediamines
  • Pyrimidines
  • RNA, Long Noncoding
  • THZ1 compound
  • Transcription Factors
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase 7, mouse
  • RNA Polymerase II
  • Cyclin-Dependent Kinase-Activating Kinase