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 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.

Details

Title
Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia
Author
Bell, Charles C 1   VIAFID ORCID Logo  ; Fennell, Katie A 1 ; Chan, Yih-Chih 1   VIAFID ORCID Logo  ; Rambow, Florian 2 ; Yeung, Miriam M 3   VIAFID ORCID Logo  ; Vassiliadis, Dane 3   VIAFID ORCID Logo  ; Lara, Luis 1 ; Yeh, Paul 4 ; Martelotto, Luciano G 5 ; Rogiers, Aljosja 6 ; Kremer, Brandon E 7 ; Barbash, Olena 7 ; Mohammad, Helai P 7 ; Johanson, Timothy M 8 ; Burr, Marian L 1   VIAFID ORCID Logo  ; Dhar, Arindam 7 ; Karpinich, Natalie 7 ; Tian, Luyi 8   VIAFID ORCID Logo  ; Tyler, Dean S 1 ; MacPherson, Laura 1 ; Shi, Junwei 9   VIAFID ORCID Logo  ; Pinnawala, Nathan 1 ; Chun Yew Fong 1 ; Papenfuss, Anthony T 10 ; Grimmond, Sean M 5   VIAFID ORCID Logo  ; Dawson, Sarah-Jane 11   VIAFID ORCID Logo  ; Allan, Rhys S 8   VIAFID ORCID Logo  ; Kruger, Ryan G 7 ; Vakoc, Christopher R 12 ; Goode, David L 1 ; Naik, Shalin H 8   VIAFID ORCID Logo  ; Omer Gilan 1 ; Lam, Enid Y N 1   VIAFID ORCID Logo  ; Jean-Christophe Marine 6 ; Prinjha, Rab K 7   VIAFID ORCID Logo  ; Dawson, Mark A 13   VIAFID ORCID Logo 

1  Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia 
2  Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium 
3  Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
4  Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
5  Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia 
6  Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium 
7  Epigenetics DPU, GlaxoSmithKline, Collegeville, Pennsylvania, USA 
8  The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; The Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia 
9  Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 
10  Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; The Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia 
11  Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia 
12  Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA 
13  Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia 
Pages
1-15
Publication year
2019
Publication date
Jun 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-10652-9
ProQuest document ID
2244136687
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.