Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
Details
Publication Year 2019-06-20, Volume 10, Issue #1, Page 2723
Journal Title
Nature Communications
Publication Type
Journal Article
Abstract
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 naive 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.
Publisher
Springer Nature
WEHI Research Division(s)
Immunology; Bioinformatics
PubMed ID
31222014
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-019-10652-9
NHMRC Grants
NHMRC/1085015 NHMRC/1106444 NHMRC/1128984
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-07-01 12:57:14
Last Modified: 2019-07-01 12:59:23
An error has occurred. This application may no longer respond until reloaded. Reload 🗙