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Dynamic induction of drug resistance through a stress-responsive enhancer in acute myeloid leukemia.

ABSTRACT: The drug efflux pump ABCB1 (ATP binding cassette subfamily B member 1) confers chemotherapy resistance in acute myeloid leukemia (AML). We recently identified an ABCB1 enhancer that is activated in response to a range of cellular stressors, including anthracycline chemotherapy. Stress drives increased ABCB1 expression and allows leukemia cells to escape from targeted third-generation ABCB1 inhibition.

SUBMITTER: Williams MS

PROVIDER: S-EPMC7051134 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dynamic induction of drug resistance through a stress-responsive enhancer in acute myeloid leukemia.

Williams Mark S MS Somervaille Tim C P TCP

Molecular & cellular oncology 20200108 2

The drug efflux pump ABCB1 (ATP binding cassette subfamily B member 1) confers chemotherapy resistance in acute myeloid leukemia (AML). We recently identified an <i>ABCB1</i> enhancer that is activated in response to a range of cellular stressors, including anthracycline chemotherapy. Stress drives increased <i>ABCB1</i> expression and allows leukemia cells to escape from targeted third-generation ABCB1 inhibition. ...[more]

PMID: 32158919

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A stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemia.

Project description:The drug efflux pump ABCB1 is a key driver of chemoresistance, and high expression predicts treatment failure in acute myeloid leukemia (AML). In this study, we identified and functionally validated the network of enhancers that controls expression of ABCB1. We show that exposure of leukemia cells to daunorubicin activated an integrated stress response-like transcriptional program to induce ABCB1 through remodeling and activation of an ATF4-bound, stress-responsive enhancer. Protracted stress primed enhancers for rapid increases in activity following re-exposure of cells to daunorubicin, providing an epigenetic memory of prior drug treatment. In primary human AML, exposure of fresh blast cells to daunorubicin activated the stress-responsive enhancer and led to dose-dependent induction of ABCB1. Dynamic induction of ABCB1 by diverse stressors, including chemotherapy, facilitated escape of leukemia cells from targeted third-generation ABCB1 inhibition, providing an explanation for the failure of ABCB1 inhibitors in clinical trials. Stress-induced upregulation of ABCB1 was mitigated by combined use of the pharmacologic inhibitors U0126 and ISRIB, which inhibit stress signaling and have potential for use as adjuvants to enhance the activity of ABCB1 inhibitors.

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Dynamic induction of drug resistance through a stress-responsive enhancer in acute myeloid leukemia

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Dynamic induction of drug resistance through a stress-responsive enhancer in acute myeloid leukemia [CHIP-seq]

Project description:The drug efflux pump ABCB1 is a key driver of chemoresistance, and high expression predicts for treatment failure in acute myeloid leukemia (AML). We show that both acute and chronic exposure of leukemia cells to daunorubicin activates an integrated stress response-like transcriptional program to induce ABCB1 through remodeling and dynamic activation of an ATF4-bound, stress-responsive enhancer. In primary human AML, stress-responsive ABCB1 enhancers are accessible and acetylated, and exposure of fresh blast cells to daunorubicin induces ABCB1 in a dose-dependent manner. Dynamic induction of ABCB1 by diverse stressors, including chemotherapy, facilitates escape of leukemia cells from targeted third-generation ABCB1 inhibition. Stress-induced up regulation of ABCB1 is mitigated by combined use of pharmacologic inhibitors U0126 and ISRIB, which inhibit stress signaling.

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