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

Author

Listed:
  • Lei Guo

    (Texas A&M University)

  • Jia Li

    (Texas A&M University)

  • Hongxiang Zeng

    (Texas A&M University)

  • Anna G. Guzman

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Tingting Li

    (Texas A&M University)

  • Minjung Lee

    (Texas A&M University)

  • Yubin Zhou

    (Texas A&M University)

  • Margaret A. Goodell

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Clifford Stephan

    (Texas A&M University)

  • Peter J. A. Davies

    (Texas A&M University)

  • Mark A Dawson

    (Peter MacCallum Cancer Centre
    University of Melbourne
    Royal Melbourne Hospital & Peter MacCallum Cancer Centre
    University of Melbourne)

  • Deqiang Sun

    (Texas A&M University)

  • Yun Huang

    (Texas A&M University)

Abstract

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.

Suggested Citation

  • Lei Guo & Jia Li & Hongxiang Zeng & Anna G. Guzman & Tingting Li & Minjung Lee & Yubin Zhou & Margaret A. Goodell & Clifford Stephan & Peter J. A. Davies & Mark A Dawson & Deqiang Sun & Yun Huang, 2020. "A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14604-6
    DOI: 10.1038/s41467-020-14604-6
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    Cited by:

    1. Faye M. Walker & Lays Martin Sobral & Etienne Danis & Bridget Sanford & Sahiti Donthula & Ilango Balakrishnan & Dong Wang & Angela Pierce & Sana D. Karam & Soudabeh Kargar & Natalie J. Serkova & Nicho, 2024. "Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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