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

Author

Listed:
  • Charles C. Bell

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Katie A. Fennell

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Yih-Chih Chan

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • 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
    University of Melbourne)

  • Paul Yeh

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    Peter MacCallum Cancer Centre)

  • Luciano G. Martelotto

    (University of Melbourne)

  • Aljosja Rogiers

    (KU Leuven
    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
    The University of Melbourne)

  • Marian L. Burr

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Arindam Dhar

    (Epigenetics DPU, GlaxoSmithKline)

  • Natalie Karpinich

    (Epigenetics DPU, GlaxoSmithKline)

  • Luyi Tian

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Dean S. Tyler

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Laura MacPherson

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Junwei Shi

    (University of Pennsylvania)

  • Nathan Pinnawala

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Chun Yew Fong

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Anthony T. Papenfuss

    (Cancer Research Division, Peter MacCallum Cancer Centre
    The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Sean M. Grimmond

    (University of Melbourne)

  • Sarah-Jane Dawson

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • Rhys S. Allan

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Ryan G. Kruger

    (Epigenetics DPU, GlaxoSmithKline)

  • Christopher R. Vakoc

    (Cold Spring Harbor)

  • David L. Goode

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Shalin H. Naik

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Omer Gilan

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Enid Y. N. Lam

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Jean-Christophe Marine

    (KU Leuven
    KU Leuven)

  • Rab K. Prinjha

    (Epigenetics DPU, GlaxoSmithKline)

  • Mark A. Dawson

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    Peter MacCallum Cancer Centre
    University of Melbourne)

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.

Suggested Citation

  • 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 Ba, 2019. "Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10652-9
    DOI: 10.1038/s41467-019-10652-9
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    Cited by:

    1. Tian Zhou & Xinyi Zhu & Zhizhong Ye & Yong-Fei Wang & Chao Yao & Ning Xu & Mi Zhou & Jianyang Ma & Yuting Qin & Yiwei Shen & Yuanjia Tang & Zhihua Yin & Hong Xu & Yutong Zhang & Xiaoli Zang & Huihua D, 2022. "Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Junyi Chen & Xiaoying Wang & Anjun Ma & Qi-En Wang & Bingqiang Liu & Lang Li & Dong Xu & Qin Ma, 2022. "Deep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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