Targeting Enhancer Switching Overcomes Non-genetic Drug Resistance in Acute Myeloid Leukaemia

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jun 22

PMID 31222014

Citations 88

Authors

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

Affiliations

Soon will be listed here.

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.

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