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; Mark A. Dawson

doi:10.1038/s41467-019-10652-9

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, Mark A. Dawson

Research output: Contribution to journal › Article › Research › peer-review

144 Citations (Scopus)

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.

Original language	English
Article number	2723
Number of pages	15
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10652-9
Publication status	Published - 20 Jun 2019
Externally published	Yes

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SDG 3 Good Health and Well-being

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Bell, C. C., Fennell, K. A., Chan, Y. C., Rambow, F., Yeung, M. M., Vassiliadis, D., Lara, L., Yeh, P., Martelotto, L. G., Rogiers, A., Kremer, B. E., Barbash, O., Mohammad, H. P., Johanson, T. M., Burr, M. L., Dhar, A., Karpinich, N., Tian, L., Tyler, D. S., ... Dawson, M. A. (2019). Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nature Communications, 10(1), Article 2723. https://doi.org/10.1038/s41467-019-10652-9

@article{74a18838f3014d8c9145347cf785fcc9,

title = "Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia",

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 na{\"i}ve 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.",

author = "Bell, \{Charles C.\} and Fennell, \{Katie A.\} and Chan, \{Yih Chih\} and Florian Rambow and Yeung, \{Miriam M.\} and Dane Vassiliadis and Luis Lara and Paul Yeh and Martelotto, \{Luciano G.\} and Aljosja Rogiers and Kremer, \{Brandon E.\} and Olena Barbash and Mohammad, \{Helai P.\} and Johanson, \{Timothy M.\} and Burr, \{Marian L.\} and Arindam Dhar and Natalie Karpinich and Luyi Tian and Tyler, \{Dean S.\} and Laura MacPherson and Junwei Shi and Nathan Pinnawala and \{Yew Fong\}, Chun and Papenfuss, \{Anthony T.\} and Grimmond, \{Sean M.\} and Sarah-Jane Dawson and Allan, \{Rhys S.\} and Kruger, \{Ryan G.\} and Vakoc, \{Christopher R.\} and Goode, \{David L.\} and Naik, \{Shalin H.\} and Omer Gilan and Lam, \{Enid Y.N.\} and Marine, \{Jean Christophe\} and Prinjha, \{Rab K.\} and Dawson, \{Mark A.\}",

note = "Funding Information: 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. Gomm{\'e} 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{\textquoteright}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). Publisher Copyright: {\textcopyright} 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = jun,

day = "20",

doi = "10.1038/s41467-019-10652-9",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Bell, CC, Fennell, KA, Chan, YC, Rambow, F, Yeung, MM, Vassiliadis, D, Lara, L, Yeh, P, Martelotto, LG, Rogiers, A, Kremer, BE, Barbash, O, Mohammad, HP, Johanson, TM, Burr, ML, Dhar, A, Karpinich, N, Tian, L, Tyler, DS, MacPherson, L, Shi, J, Pinnawala, N, Yew Fong, C, Papenfuss, AT, Grimmond, SM, Dawson, S-J, Allan, RS, Kruger, RG, Vakoc, CR, Goode, DL, Naik, SH, Gilan, O, Lam, EYN, Marine, JC, Prinjha, RK & Dawson, MA 2019, 'Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia', Nature Communications, vol. 10, no. 1, 2723. https://doi.org/10.1038/s41467-019-10652-9

TY - JOUR

T1 - Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia

AU - Bell, Charles C.

AU - Fennell, Katie A.

AU - Chan, Yih Chih

AU - Rambow, Florian

AU - Yeung, Miriam M.

AU - Vassiliadis, Dane

AU - Lara, Luis

AU - Yeh, Paul

AU - Martelotto, Luciano G.

AU - Rogiers, Aljosja

AU - Kremer, Brandon E.

AU - Barbash, Olena

AU - Mohammad, Helai P.

AU - Johanson, Timothy M.

AU - Burr, Marian L.

AU - Dhar, Arindam

AU - Karpinich, Natalie

AU - Tian, Luyi

AU - Tyler, Dean S.

AU - MacPherson, Laura

AU - Shi, Junwei

AU - Pinnawala, Nathan

AU - Yew Fong, Chun

AU - Papenfuss, Anthony T.

AU - Grimmond, Sean M.

AU - Dawson, Sarah-Jane

AU - Allan, Rhys S.

AU - Kruger, Ryan G.

AU - Vakoc, Christopher R.

AU - Goode, David L.

AU - Naik, Shalin H.

AU - Gilan, Omer

AU - Lam, Enid Y.N.

AU - Marine, Jean Christophe

AU - Prinjha, Rab K.

AU - Dawson, Mark A.

N1 - Funding Information: 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. Gommé 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). Publisher Copyright: © 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/6/20

Y1 - 2019/6/20

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85067593722

U2 - 10.1038/s41467-019-10652-9

DO - 10.1038/s41467-019-10652-9

M3 - Article

C2 - 31222014

AN - SCOPUS:85067593722

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2723

ER -

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

Abstract

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