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Cancer Discov. 2019 Jul;9(7):872-889. doi: 10.1158/2159-8290.CD-19-0106. Epub 2019 May 10.

Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML.

Author information

1
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York. amm2014@med.cornell.edu carroll2@pennmedicine.upenn.edu cid2001@med.cornell.edu.
2
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York.
3
Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.
4
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia.
5
Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
6
Memorial Sloan Kettering Cancer Center, New York, New York.
7
GlaxoSmithKline, Collegeville, Pennsylvania.
8
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
9
Oncology, Montefiore Medical Center, Bronx, New York.
10
Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. amm2014@med.cornell.edu carroll2@pennmedicine.upenn.edu cid2001@med.cornell.edu.
11
Department of Pharmacology, Weill Cornell Medicine, New York, New York.

Abstract

Disruption of epigenetic regulation is a hallmark of acute myeloid leukemia (AML), but epigenetic therapy is complicated by the complexity of the epigenome. Herein, we developed a long-term primary AML ex vivo platform to determine whether targeting different epigenetic layers with 5-azacytidine and LSD1 inhibitors would yield improved efficacy. This combination was most effective in TET2 mut AML, where it extinguished leukemia stem cells and particularly induced genes with both LSD1-bound enhancers and cytosine-methylated promoters. Functional studies indicated that derepression of genes such as GATA2 contributes to drug efficacy. Mechanistically, combination therapy increased enhancer-promoter looping and chromatin-activating marks at the GATA2 locus. CRISPRi of the LSD1-bound enhancer in patient-derived TET2 mut AML was associated with dampening of therapeutic GATA2 induction. TET2 knockdown in human hematopoietic stem/progenitor cells induced loss of enhancer 5-hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. Our data provide a basis for rational targeting of cooperating aberrant promoter and enhancer epigenetic marks driven by mutant epigenetic modifiers. SIGNIFICANCE: Somatic mutations of genes encoding epigenetic modifiers are a hallmark of AML and potentially disrupt many components of the epigenome. Our study targets two different epigenetic layers at promoters and enhancers that cooperate to aberrant gene silencing, downstream of the actions of a mutant epigenetic regulator.This article is highlighted in the In This Issue feature, p. 813.

PMID:
31076479
PMCID:
PMC6606333
[Available on 2020-07-01]
DOI:
10.1158/2159-8290.CD-19-0106

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