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TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Nature volume 463, pages 676–680 (2010)Cite this article

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Abstract

Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase1. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells2,3,4. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML5,6,7,8. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a+/+ and Foxo3a-/- mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-β is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-β inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-β inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-β–FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.

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Figure 1: Maintenance of CML LICs depends on Foxo3a.
Figure 2: Essential role of Foxo3a in suppression of LIC apoptosis.
Figure 3: TGF-β–Foxo signalling is required for the colony-forming capacity of LICs.
Figure 4: Inhibition of TGF-β–Foxo3a signalling in combination with TKI therapy depletes CML in vivo.

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Acknowledgements

We thank H. Honda for BCR-ABL cDNA, C. A. Schmitt for MSCV-dnFoxo-ires-GFP, T. Nakamura for MSCV-NUP98-HOXA9, T. Kitamura for Plat-E retroviral packaging cells, T. Suda, N. Komatsu and K. Miyazono for discussions, and M. Sakae and T. Hatakeyama for expert technical support. We also thank Novartis International AG for imatinib (STI571). K.N. was supported by a grant-in-aid for Scientific Research (C), and A.H. was supported by grants-in-aid for Scientific Research (B) and Creative Scientific Research (17GS0419) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author Contributions K.N. designed research, performed experiments, analysed data, and co-wrote the paper. T.H., T.M., Y.T, T.O. and N.M. performed experiments. Y.K. and S.N. provided technical support for the human cell experiments. A.H. designed research, analysed data and co-wrote the paper.

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  1. Kazuhito Naka and Takayuki Hoshii: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan,

    Kazuhito Naka, Takayuki Hoshii, Teruyuki Muraguchi, Yuko Tadokoro, Takako Ooshio & Atsushi Hirao

  2. Core Research for Evolution Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0075, Japan ,

    Takako Ooshio & Atsushi Hirao

  3. Division of Cancer Medicine, Cellular Transplantation Biology, Kanazawa University, Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan,

    Yukio Kondo & Shinji Nakao

  4. Department of Geriatric Medicine, National Institute for Longevity Sciences, National Center for Gerontology and Geriatrics, Obu, Aichi 474-8522, Japan,

    Noboru Motoyama

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  1. Kazuhito Naka
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Correspondence to Kazuhito Naka or Atsushi Hirao.

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Naka, K., Hoshii, T., Muraguchi, T. et al. TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676–680 (2010). https://doi.org/10.1038/nature08734

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