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A Combination Strategy Targeting Enhancer Plasticity Exerts Synergistic Lethality Against Beti-Resistant Leukemia Cells
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020), Nature Communications
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
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.<br />Epigenetic changes can drive drug resistance in cancer. Here, the authors show that in BET inhibitor resistant leukaemia cells, genome-wide enhancer remodelling drives therapeutic resistance and targeting enhancer plasticity may overcome this resistance.
- Subjects :
- 0301 basic medicine
Genes, myc
General Physics and Astronomy
Cell Cycle Proteins
Phenylenediamines
Jurkat cells
Biochemistry
Jurkat Cells
Mice
0302 clinical medicine
lcsh:Science
0303 health sciences
Multidisciplinary
Nuclear Proteins
Gene silencing
Drug Synergism
Hematology
Cyclin-Dependent Kinases
PVT1
3. Good health
Chromatin
Enhancer Elements, Genetic
030220 oncology & carcinogenesis
Female
RNA, Long Noncoding
RNA Polymerase II
BRD4
Science
Immunology
Biology
Heterocyclic Compounds, 4 or More Rings
Article
Acute myeloid leukaemia
General Biochemistry, Genetics and Molecular Biology
BET inhibitor
03 medical and health sciences
Histone H3
Distal Enhancer Elements
Cell Line, Tumor
Animals
Humans
Enhancer
Transcription factor
030304 developmental biology
Leukemia, Experimental
Models, Genetic
General Chemistry
Cell Biology
Bromodomain
Pyrimidines
030104 developmental biology
Drug Resistance, Neoplasm
Cancer cell
Cancer research
lcsh:Q
K562 Cells
Cyclin-Dependent Kinase-Activating Kinase
Transcription Factors
K562 cells
030215 immunology
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....cd5724787f8db8ee264521450f0925ec