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Blood. 2018 Apr 12;131(15):1730-1742. doi: 10.1182/blood-2017-09-807024. Epub 2018 Feb 16.

LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML.

Author information

1
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
2
University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
3
GlaxoSmithKline, Newark, NJ.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute, and.
5
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
6
Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY; and.
7
Imago Biosciences, Inc., San Francisco, CA.

Abstract

Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine-specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML. We performed a comparative assessment of chromatin dynamics during the treatment of mixed lineage leukemia (MLL)-AF9-driven murine leukemias and MLL-rearranged patient-derived xenografts using 2 distinct but effective differentiation-inducing targeted epigenetic therapies, the LSD1 inhibitor GSK-LSD1 and the DOT1L inhibitor EPZ4777. Intriguingly, GSK-LSD1 treatment caused global gains in chromatin accessibility, whereas treatment with EPZ4777 caused global losses in accessibility. We captured PU.1 and C/EBPα motif signatures at LSD1 inhibitor-induced dynamic sites and chromatin immunoprecipitation coupled with high-throughput sequencing revealed co-occupancy of these myeloid transcription factors at these sites. Functionally, we confirmed that diminished expression of PU.1 or genetic deletion of C/EBPα in MLL-AF9 cells generates resistance of these leukemias to LSD1 inhibition. These findings reveal that pharmacologic inhibition of LSD1 represents a unique path to overcome the differentiation block in AML for therapeutic benefit.

PMID:
29453291
PMCID:
PMC5897868
[Available on 2019-04-12]
DOI:
10.1182/blood-2017-09-807024

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