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Acute myeloid leukemia

LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia

Leukemia volume 34, pages 746–758 (2020)Cite this article

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Abstract

Super-enhancers (SEs) consist of enhancer clusters with abundant binding of transcription factors (TFs) and cofactors. LSD1 is a histone modifier that eliminates SE activity. However, whether SE suppression by LSD1 is associated with leukemogenesis remains unknown. In erythro–megakaryocyte lineage leukemia cells, activation of the SE of GFI1 (GFI1-SE) is related to induction of myeloid differentiation by LSD1 inhibitors NCD38 and NCD25 and to their antileukemia effect. Although functional TF-motifs were concentrated in an evolutionally conserved area, NCD38 barely induced additional TF recruitment. Instead, the transcription cofactors including LSD1, CoREST, HDAC1, and HDAC2 were evicted from GFI1-SE. Deletion of GFI1-SE impaired induction of myeloid differentiation by NCD38 and NCD25 in erythroleukemia cells. Gene set enrichment analysis revealed that the GFI1-SE deletion impaired NCD38-induced programs related to granulocyte differentiation and the CEBPA network, but restored NCD38-suppressed programs related to erythroid development, GATA1 targets, and acute myeloid leukemia (AML) clusters including FAB subtype M6 and AML with myelodysplastic syndrome-related chromosomal abnormalities. Ontologies of genes whose expression changes by NCD38 were canceled due to the GFI1-SE deletion showed enrichment in AML and neutropenia signatures. Collectively, our data suggest that sustainable repression of GFI1-SE by LSD1 is essential for sustenance of erythroleukemia cells.

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Acknowledgements

We would like to thank Hideyo Hirai (Department of Transfusion Medicine and Cell Therapy, Kyoto University) for help with vector construction. We also thank the Central Research Laboratory of Shiga University of Medical Science for assistance with quantitative PCR and the AMAXA transfection system. This work was supported by JSPS KAKENHI Grant Number JP16K09846 (MK) and the Takeda Science Foundation (MK).

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Authors and Affiliations

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

    Goichi Tatsumi, Ryusuke Yamamoto, Masakatsu Hishizawa & Akifumi Takaori-Kondo

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

    Goichi Tatsumi, Masahiro Kawahara, Katsuyuki Kito & Akira Andoh

  3. The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan

    Takayoshi Suzuki

  4. CREST, Japan Science and Technology Agency (JST), Kawaguchi, Japan

    Takayoshi Suzuki

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  1. Goichi Tatsumi
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GT performed all experiments, analyzed data, and wrote the paper. MK designed and conducted all experiments, analyzed data, provided funding, and wrote the paper. RY and MH assisted with several experiments. TS provided LSD1 inhibitors. KK, AT-K and AA supervised the experiments and edited the paper.

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Correspondence to Masahiro Kawahara.

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Tatsumi, G., Kawahara, M., Yamamoto, R. et al. LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia. Leukemia 34, 746–758 (2020). https://doi.org/10.1038/s41375-019-0614-6

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