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

Lei Guo1, Jia Li1, Hongxiang Zeng1

  • 1Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, 77030, USA.

Nature Communications
|February 8, 2020
PubMed

Insights

Drug resistance in cancer is linked to epigenetic changes. Researchers found targeting enhancer plasticity, like the PVT1 enhancer, can overcome resistance to epigenetic therapies in leukemia.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Molecular Oncology

Background:

  • Drug resistance, particularly acquired resistance, is a major challenge in cancer therapy.
  • Epigenetic modifications play a crucial role in the development of tumor cell drug resistance.

Purpose of the Study:

  • To investigate the role of genome-wide enhancer remodeling in driving therapeutic resistance in leukemia.
  • To identify novel mechanisms and potential therapeutic targets to overcome drug resistance.

Main Methods:

  • Utilized BET inhibitor (BETi)-resistant leukemia cells as a model system.
  • Employed CRISPR interference technology to identify regulatory elements.
  • Investigated the role of enhancer elements in gene transcription and drug resistance.

Main Results:

  • Demonstrated that enhancer remodeling drives therapeutic resistance through re-expression of pro-survival genes.
  • Identified a gained enhancer within the second intron of IncRNA PVT1 that restores MYC transcription independent of BRD4.
  • Showed that combined BETi and CDK7 inhibitor treatment blocks MYC transcription by inhibiting RNAPII loading.

Conclusions:

  • Established enhancer plasticity as a key mechanism in therapeutic resistance.
  • Highlighted the potential of targeting enhancer plasticity to overcome resistance to epigenetic therapies.
  • Validated a combined BETi and CDK7 inhibitor strategy to abolish MYC transcription in resistant leukemia cells.

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