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Acute myeloid leukemia

A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers

Leukemia volume 31, pages 2303–2314 (2017)Cite this article

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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.

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Acknowledgements

We are grateful to Dr Toshio Kitamura (University of Tokyo) for kindly gifting the vectors and providing scientific comments and to Dr Kaoru Tohyama (Kawasaki Medical School) and Dr Akihiko Yokoyama (Kyoto University) for kindly gifting the cell lines and providing scientific comments. This work was supported by the JSPS KAKENHI grant numbers JP25118713 and JP16K09846 (MK), the Kanae Foundation for the promotion of medical science (MK), and the Takeda Science Foundation (MK). This work was carried out at the Joint Usage/Research Center (RIRBM), Hiroshima University. This work was funded by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MK), the Kanae Foundation for the promotion of medical science (MK), and the Takeda Science Foundation (MK).

Author contributions

NS performed and analyzed most of experiments and wrote the manuscript. MK obtained grants, organized the project, designed and analyzed all experiments, and wrote the manuscript. GT performed and analyzed the ChIP experiments and GFI1-knockout experiments. AK, HM and TI performed and analyzed the ChIP-seq. RY performed WB. YN, SF, YS and MH assisted with some experiments. TS provided the compounds. AA and AT supervised the project.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    N Sugino, M Kawahara, G Tatsumi, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa & A Takaori-Kondo

  2. Department of Medicine, Shiga University of Medical Science, Otsu, Japan

    M Kawahara & A Andoh

  3. Department of Molecular Oncology and Leukemia Program Project, Hiroshima University, Hiroshima, Japan

    A Kanai, H Matsui & T Inaba

  4. Department of Molecular Laboratory Medicine, Kumamoto University, Kumamoto, Japan

    H Matsui

  5. Department of Chemistry, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

    T Suzuki

  6. CREST, Japan Science and Technology Agency (JST), Tokyo, Japan

    T Suzuki

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  1. N Sugino
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Correspondence to M Kawahara.

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Sugino, N., Kawahara, M., Tatsumi, G. et al. A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. Leukemia 31, 2303–2314 (2017). https://doi.org/10.1038/leu.2017.59

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