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; Yun Huang

doi:10.1038/s41467-020-14604-6

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, Yun Huang

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English (US)
Article number	740
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14604-6
State	Published - Dec 1 2020
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-020-14604-6

Cite this

@article{a38d3f5307bf470c875a9f1a57d6b1e4,

title = "A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells",

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.",

author = "Lei Guo and Jia Li and Hongxiang Zeng and Guzman, {Anna G.} and Tingting Li and Minjung Lee and Yubin Zhou and Goodell, {Margaret A.} and Clifford Stephan and Davies, {Peter J.A.} and Dawson, {Mark A.} and Deqiang Sun and Yun Huang",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-14604-6",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells

AU - Guo, Lei

AU - Li, Jia

AU - Zeng, Hongxiang

AU - Guzman, Anna G.

AU - Li, Tingting

AU - Lee, Minjung

AU - Zhou, Yubin

AU - Goodell, Margaret A.

AU - Stephan, Clifford

AU - Davies, Peter J.A.

AU - Dawson, Mark A.

AU - Sun, Deqiang

AU - Huang, Yun

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85079080402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85079080402&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-14604-6

DO - 10.1038/s41467-020-14604-6

M3 - Article

C2 - 32029739

AN - SCOPUS:85079080402

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 740

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this