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

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., MacPherson, L., Shi, J., Pinnawala, N., Yew Fong, C., Papenfuss, A. T., Grimmond, S. M., Dawson, S. J., Allan, R. S., Kruger, R. G., Vakoc, C. R., Goode, D. L., Naik, S. H., Gilan, O., Lam, E. Y. N., Marine, J. C., Prinjha, R. K., Dawson, M. A. (June 2019) Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nat Commun, 10 (1). p. 2723. ISSN 2041-1723

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URL: https://www.ncbi.nlm.nih.gov/pubmed/31222014
DOI: 10.1038/s41467-019-10652-9

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 naive 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.

Item Type: Paper
Subjects: Investigative techniques and equipment > CRISPR-Cas9
diseases & disorders > cancer > cancer types > leukemia
Investigative techniques and equipment > assays > RNA-seq
CSHL Authors:
Communities: CSHL labs > Vakoc lab
Depositing User: Matthew Dunn
Date: 20 June 2019
Date Deposited: 08 Aug 2019 13:36
Last Modified: 08 Aug 2019 13:36
PMCID: PMC6586637
Related URLs:
URI: http://repository.cshl.edu/id/eprint/38137

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