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

Charles C. Bell, Katie A. Fennell, Yih-Chih Chan, Florian Rambow, Miriam M. Yeung, Dane Vassiliadis, Luis Lara, Paul Yeh, Luciano G. Martelotto, Aljosja Rogiers, Brandon E. Kremer, Olena Barbash, Helai P. Mohammad, Timothy M. Johanson, Marian L. Burr, Arindam Dhar, Natalie Karpinich, Luyi Tian, Dean S. Tyler, Laura MacPherson, Junwei Shi, Nathan Pinnawala, Chun Yew Fong, Anthony T. Papenfuss, Sean M. Grimmond, Sarah-Jane Dawson, Rhys S. Allan, Ryan G. Kruger, Christopher R. Vakoc, David L. Goode, Shalin H. Naik, Omer Gilan, Enid Y. N. Lam, Jean-Christophe Marine, Rab K. Prinjha and Mark A. Dawson ()
Additional contact information
Charles C. Bell: Cancer Research Division, Peter MacCallum Cancer Centre
Katie A. Fennell: Cancer Research Division, Peter MacCallum Cancer Centre
Yih-Chih Chan: Cancer Research Division, Peter MacCallum Cancer Centre
Florian Rambow: KU Leuven
Miriam M. Yeung: Cancer Research Division, Peter MacCallum Cancer Centre
Dane Vassiliadis: Cancer Research Division, Peter MacCallum Cancer Centre
Luis Lara: Cancer Research Division, Peter MacCallum Cancer Centre
Paul Yeh: Cancer Research Division, Peter MacCallum Cancer Centre
Luciano G. Martelotto: University of Melbourne
Aljosja Rogiers: KU Leuven
Brandon E. Kremer: Epigenetics DPU, GlaxoSmithKline
Olena Barbash: Epigenetics DPU, GlaxoSmithKline
Helai P. Mohammad: Epigenetics DPU, GlaxoSmithKline
Timothy M. Johanson: The Walter and Eliza Hall Institute of Medical Research
Marian L. Burr: Cancer Research Division, Peter MacCallum Cancer Centre
Arindam Dhar: Epigenetics DPU, GlaxoSmithKline
Natalie Karpinich: Epigenetics DPU, GlaxoSmithKline
Luyi Tian: The Walter and Eliza Hall Institute of Medical Research
Dean S. Tyler: Cancer Research Division, Peter MacCallum Cancer Centre
Laura MacPherson: Cancer Research Division, Peter MacCallum Cancer Centre
Junwei Shi: University of Pennsylvania
Nathan Pinnawala: Cancer Research Division, Peter MacCallum Cancer Centre
Chun Yew Fong: Cancer Research Division, Peter MacCallum Cancer Centre
Anthony T. Papenfuss: Cancer Research Division, Peter MacCallum Cancer Centre
Sean M. Grimmond: University of Melbourne
Sarah-Jane Dawson: Cancer Research Division, Peter MacCallum Cancer Centre
Rhys S. Allan: The Walter and Eliza Hall Institute of Medical Research
Ryan G. Kruger: Epigenetics DPU, GlaxoSmithKline
Christopher R. Vakoc: Cold Spring Harbor
David L. Goode: Cancer Research Division, Peter MacCallum Cancer Centre
Shalin H. Naik: The Walter and Eliza Hall Institute of Medical Research
Omer Gilan: Cancer Research Division, Peter MacCallum Cancer Centre
Enid Y. N. Lam: Cancer Research Division, Peter MacCallum Cancer Centre
Jean-Christophe Marine: KU Leuven
Rab K. Prinjha: Epigenetics DPU, GlaxoSmithKline
Mark A. Dawson: Cancer Research Division, Peter MacCallum Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10652-9

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