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

Monica Cusan, Sheng F. Cai, Helai Mohammad, Andrei Krivtsov, Alan Chramiec, Evangelia Loizou, Matthew D. Witkin, Kimberly N. Smitheman, Daniel G. Tenen, Min Ye, Britta Will, Ulrich Steidl, Ryan G. Kruger, Ross L. Levine, Hugh Y. Rienhoff, Richard P. Koche, Scott A. Armstrong

Research output: Contribution to journalArticle

24 Scopus citations

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/EBPa 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/EBPa 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.

Original languageEnglish (US)
Pages (from-to)1730-1742
Number of pages13
JournalBlood
Volume131
Issue number15
DOIs
StatePublished - Apr 12 2018

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Cusan, M., Cai, S. F., Mohammad, H., 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., Koche, R. P., & Armstrong, S. A. (2018). LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPa-dependent enhancers in AML. Blood, 131(15), 1730-1742. https://doi.org/10.1182/blood-2017-09-807024