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Acute Leukemias

Hes1 suppresses acute myeloid leukemia development through FLT3 repression

Leukemia volume 29, pages 576–585 (2015)Cite this article

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Abstract

In leukemogenesis, Notch signaling can be up and downregulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well-characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix–loop–helix-type protein, and represses target gene expression. Here, we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL–AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. FLT3 was consequently upregulated in MLL–AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL–AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL–AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL–AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing messenger RNA (mRNA) expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by downregulating FLT3 expression.

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Acknowledgements

We thank Drs T Machino and T Enami (University of Tsukuba) for discussion; Drs A Yokoyama (Kyoto University), H Nakauchi (University of Tokyo/Stanford University), and, M Onodera (National Research Institute for Child Health and Development) for vectors. We also thank T Takahashi for mouse experiments. We are also grateful to Kyowa Hakko Kirin Co., Ltd. for KRN383. This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (25860778 to TK; 25461407 to MS-Y; and 25112703, 24390241, 23118503 and 22130002 to SC) and supported by the Sagawa Cancer Foundation, the Naito Foundation, the Kato Memorial Bioscience Foundation and the YASUDA Medical Foundation to MS-Y.

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Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    T Kato, M Sakata-Yanagimoto, H Nishikii, Y Yokoyama, H Muto, N Obara, K Suzukawa, Y Hasegawa & S Chiba

  2. Life Science center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan

    T Kato & S Chiba

  3. Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    T Kato, M Sakata-Yanagimoto, Y Miyake, Y Asabe, Y Kamada, H Muto, N Obara, Y Hasegawa & S Chiba

  4. Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    M Ueno & A Hirao

  5. Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan

    I Kitabayashi

  6. Department of Molecular Biological Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    K Uchida

  7. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

    H Yagita

  8. Institute of Virus Research, Kyoto University, Kyoto, Japan

    R Kageyama

  9. World Premier International Research Initiative-Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan

    R Kageyama

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Correspondence to S Chiba.

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Kato, T., Sakata-Yanagimoto, M., Nishikii, H. et al. Hes1 suppresses acute myeloid leukemia development through FLT3 repression. Leukemia 29, 576–585 (2015). https://doi.org/10.1038/leu.2014.281

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