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 |
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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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