Journal
BLOOD
Volume 131, Issue 15, Pages 1730-1742Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-09-807024
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Funding
- German Research Council (DFG) within the Collaborative Research Centre (SFB) Cancer Evolution [1243]
- Young Investigator Award from the Conquer Cancer Foundation
- Career Development Program Fellow Award from the Leukemia & Lymphoma Society
- Memorial Sloan-Kettering Cancer Center Clinical Scholars Biomedical Research Fellowship
- National Institutes of Health (NIH), National Cancer Institute [PO1 CA66996, R01 CA140575]
- Gabrielle's Angel Research Foundation
- NIH Memorial Sloan-Kettering Cancer Center Support Grant from the National Cancer Institute [P30 CA008748]
- NIH/National Cancer Institute Cancer Center Support Grant [P30 CA008748]
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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/EBP alpha 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/EBP alpha 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.
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