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

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 () and Yun Huang ()
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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
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
Clifford Stephan: Texas A&M University
Peter J. A. Davies: Texas A&M University
Mark A Dawson: Peter MacCallum Cancer Centre
Deqiang Sun: Texas A&M University
Yun Huang: Texas A&M University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14604-6

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