title: A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers.
abstract: Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sugino
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: M
authors.identifier: 0000-0002-2721-7571
authors.initials: M
authors.lastname: Kawahara
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Tatsumi
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Hiroshima University, Hiroshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Hiroshima University, Hiroshima, Japan.|Department of Molecular Laboratory Medicine, Kumamoto University, Kumamoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shimazu
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hishizawa
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Hiroshima University, Hiroshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Andoh
authors.affiliation: Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.|CREST, Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: A
authors.identifier: 0000-0001-7678-4284
authors.initials: A
authors.lastname: Takaori-Kondo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D009190:Myelodysplastic Syndromes / Q000150:complications*
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; C000625214:NCD38 compound; D056466:Histone Demethylases; C495195:KDM1A protein, human