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LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML.
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; Koche, Richard P; Armstrong, Scott A.
Afiliación
  • Cusan M; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Cai SF; University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
  • Mohammad HP; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Krivtsov A; GlaxoSmithKline, Newark, NJ.
  • Chramiec A; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Loizou E; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and.
  • Witkin MD; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Smitheman KN; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Tenen DG; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Ye M; GlaxoSmithKline, Newark, NJ.
  • Will B; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
  • Steidl U; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
  • Kruger RG; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY; and.
  • Levine RL; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY; and.
  • Rienhoff HY; GlaxoSmithKline, Newark, NJ.
  • Koche RP; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY.
  • Armstrong SA; Imago Biosciences, Inc., San Francisco, CA.
Blood ; 131(15): 1730-1742, 2018 04 12.
Article en En | MEDLINE | ID: mdl-29453291
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Bifenotípica Aguda / Transactivadores / Proteínas Proto-Oncogénicas / Proteínas Potenciadoras de Unión a CCAAT / Inhibidores Enzimáticos / Histona Demetilasas / Proteínas de Neoplasias / Neoplasias Experimentales Límite: Animals Idioma: En Revista: Blood Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Bifenotípica Aguda / Transactivadores / Proteínas Proto-Oncogénicas / Proteínas Potenciadoras de Unión a CCAAT / Inhibidores Enzimáticos / Histona Demetilasas / Proteínas de Neoplasias / Neoplasias Experimentales Límite: Animals Idioma: En Revista: Blood Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos