Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia

Autor: Luciano G. Martelotto, Mark A. Dawson, Paul Yeh, Jean-Christophe Marine, David L Goode, Charles C. Bell, Christopher R. Vakoc, Brandon E. Kremer, Rab K. Prinjha, Sean M. Grimmond, Enid Y.N. Lam, Olena Barbash, Laura MacPherson, Helai P. Mohammad, Chun Yew Fong, Nathan Pinnawala, Timothy M. Johanson, Katie A Fennell, Aljosja Rogiers, Marian L. Burr, Sarah-Jane Dawson, Florian Rambow, Ryan G. Kruger, Shalin H. Naik, Yih-Chih Chan, Anthony T. Papenfuss, Dane Vassiliadis, Rhys S. Allan, Luis Lara, Junwei Shi, Omer Gilan, Arindam Dhar, Luyi Tian, Natalie Karpinich, Miriam M. Yeung, Dean Tyler
Přispěvatelé: Bell, Charles C [0000-0003-2194-8311], Chan, Yih-Chih [0000-0003-2177-5406], Yeung, Miriam M [0000-0002-9455-1887], Vassiliadis, Dane [0000-0002-7814-4851], Burr, Marian L [0000-0002-8995-3398], Tian, Luyi [0000-0003-3420-3685], Shi, Junwei [0000-0002-8427-6316], Grimmond, Sean M [0000-0002-8102-7998], Dawson, Sarah-Jane [0000-0002-8276-0374], Allan, Rhys S [0000-0003-0906-2980], Naik, Shalin H [0000-0003-0299-3301], Lam, Enid YN [0000-0001-5843-7836], Prinjha, Rab K [0000-0002-2666-3326], Dawson, Mark A [0000-0002-5464-5029], Apollo - University of Cambridge Repository
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
CHROMATIN
Transcription
Genetic
TRANSCRIPTIONAL PROGRAM
General Physics and Astronomy
02 engineering and technology
Drug resistance
Kaplan-Meier Estimate
Epigenesis
Genetic
Mice
Single-cell analysis
Bone Marrow
PLASTICITY
lcsh:Science
Regulation of gene expression
Multidisciplinary
Gene Expression Regulation
Leukemic
021001 nanoscience & nanotechnology
CLONAL EVOLUTION
CANCER
Chromatin
3. Good health
Multidisciplinary Sciences
Leukemia
Myeloid
Acute
Treatment Outcome
Mechanisms of disease
Science & Technology - Other Topics
Female
Epigenetics
Single-Cell Analysis
0210 nano-technology
STEM-CELLS
BRD4
Science
Antineoplastic Agents
Computational biology
Biology
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Cell Line
Tumor
Animals
Humans
Enhancer
Haematological cancer
Science & Technology
Sequence Analysis
RNA
MUTATIONS
Pioneer factor
PU.1
General Chemistry
DNA
Xenograft Model Antitumor Assays
Gene regulation
Mice
Inbred C57BL
030104 developmental biology
HEK293 Cells
MAINTENANCE
Drug Resistance
Neoplasm
Trans-Activators
lcsh:Q
IRF8
CRISPR-Cas Systems
Zdroj: Nature Communications
Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019)
Popis: Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.
There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.
Databáze: OpenAIRE
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