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Cusan, Monica; Cai, Sheng F.; Mohammad, Helai P.; Krivtsov, Andrei; Chramiec, Alan; Loizou, Evangelia; Witkin, Matthew D.; Smitheman, Kimberly N.; Tenen, Daniel G.; Ye, Min; Will, Britta; Steidl, Ulrich; Kruger, Ryan G.; Levine, Ross L.; Rienhoff, Hugh Y. Jr.; Koche, Richard P.; Armstrong, Scott A. (2018): LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1-and C/EBP alpha-dependent enhancers in AML. In: Blood, Vol. 131, No. 15: pp. 1730-1742
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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.