Journal article

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 JA Davies, Mark A Dawson, Deqiang Sun, Yun Huang

Nature Communications | NATURE PUBLISHING GROUP | Published : 2020

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 BET..

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Grants

Awarded by MD Anderson Cancer Center next-generation sequencing core at Smithville


Awarded by Cancer Prevention and Research Institute of Texas


Awarded by National Institute of Health


Awarded by Welch Foundation


Awarded by American Cancer Society


Funding Acknowledgements

The authors are grateful for Dr. Jianjun Shen and the MD Anderson Cancer Center next-generation sequencing core at Smithville (CPRIT RP120348 and RP170002), and the Epigenetic core in the Institute of Biosciences and Technology at the Texas A& M University. This work was supported by grants from Cancer Prevention and Research Institute of Texas (RR140053 to Y.H., to RP170660 to Y.Z., RP180131 to D.S., RP150578 to C. S. and P.D.), National Institute of Health grants (R01HL134780 and R01HL146852 to Y.H., R01GM112003 and R01CA232017 to Y.Z.), the Welch Foundation (BE-1913-20190330 to Y.Z.), the John S. Dunn Foundation (to Y.H.), the American Cancer Society (RSG-18-043-01-LIB to YH; RSG-16-215-01-TBE to Y.Z.), Cancer Fighter of Houston to Y.H., and by an allocation from the Texas A&M University start-up funds (Y.H. and D.S.).