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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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:	diseases & disorders > cancer diseases & disorders Investigative techniques and equipment diseases & disorders > cancer > cancer types > acute myeloid leukemia organism description > animal Investigative techniques and equipment > assays organs, tissues, organelles, cell types and functions > organs types and functions > bone marrow organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions Investigative techniques and equipment > CRISPR-Cas9 diseases & disorders > cancer > cancer types > leukemia organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions Investigative techniques and equipment > assays > RNA-seq organism description > animal > mammal > rodent diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User:	Matthew Dunn
Date:	20 June 2019
Date Deposited:	08 Aug 2019 13:36
Last Modified:	01 Feb 2024 20:30
PMCID:	PMC6586637
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38137

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