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

Authors: Cusan, M.; Cai, S. F.; Mohammad, H. P.; Krivtsov, A.; Chramiec, A.; Loizou, E.; Witkin, M. D.; Smitheman, K. N.; Tenen, D. G.; Ye, M.; Will, B.; Steidl, U.; Kruger, R. G.; Levine, R. L.; Rienhoff, H. Y. Jr; Koche, R. P.; Armstrong, S. A.
Article Title: LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML
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/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.
Keywords: differentiation; expression; stem-cells; colony-stimulating factor; poor-prognosis; acute myeloid-leukemia; pharmacological inhibition; cancer; h3k79 methylation; demethylase 1
Journal Title: Blood
Volume: 131
Issue: 15
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-04-12
Start Page: 1730
End Page: 1742
Language: English
ACCESSION: WOS:000430688700016
DOI: 10.1182/blood-2017-09-807024
PMCID: PMC5897868
PUBMED: 29453291
Notes: Article -- Source: Wos
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MSK Authors
  1. Ross Levine
    469 Levine
  2. Sheng Feng Cai
    7 Cai
  3. Scott Allen Armstrong
    108 Armstrong
  4. Monica Cusan
    12 Cusan
  5. Richard Patrick Koche
    48 Koche
  6. Matthew David Witkin
    7 Witkin
  7. Evangelia   Loizou
    4 Loizou