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

Charles C Bell; Katie A Fenne; 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 YN Lam; Jean-Christophe Marine; Rab K Prinjha; Mark A Dawson

Journal article

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

Charles C Bell, Katie A Fenne, 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 Show all

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2019

DOI: 10.1038/s41467-019-10652-9

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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 pione..

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University of Melbourne Researchers

Mark Dawson Author

Chih Chan Author The Sir Peter Maccallum Department of Oncology

Rhys Allan Author Medical Biology (w.e.h.i.)

Sarah-Jane Dawson Author

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Awarded by Howard Hughes Medical Institute international research scholarship

Awarded by NHMRC

Awarded by Maddie Riewoldt's Vision

Awarded by FWO

Awarded by National Health and Medical Research Council of Australia

Funding Acknowledgements

We thank Gisela Arnau, Tim Semple, Jake Carmody and Tim Holloway for advice and assistance with genomic sequencing, Susan Jackson, Kimberly Smitheman and Jacob Rubin for experimental assistance and the members of the Dawson lab for experimental assistance, helpful comments and input into the manuscript. We thank O. Van Goethem for excellent technical assistance; PDX experiments were developed by TRACE with assistance of E. Leucci, L. Rizzotto, D. Thomas, E. Gomme and K. Crevits. The Tru-Sight26 analysis was performed by S. Vander Borght. We thank the following funders for Fellowship, Scholarship and grant support - Leukaemia Foundation Australia senior fellowship and Howard Hughes Medical Institute international research scholarship 55008729 (M.A.D.), CSL Centenary fellowship (S.-J.D.), NHMRC grant 1085015, 1106444 (M.A.D) and 1128984 (M.A.D, S.-J.D.), Snowdome Foundation (P.Y., M.A.D.), Maddie Riewoldt's Vision 064728 (Y.-C.C.), Victorian Cancer Agency (E.Y.N.L., L.M.), CRUK (M.L.B.) and FWO #G.0929.16 N (J.-C.M).