Nature 463, 676-680 (4 February 2010) | doi:10.1038/nature08734; Received 9 March 2009; Accepted 4 December 2009

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

Kazuhito Naka1,5, Takayuki Hoshii1,5, Teruyuki Muraguchi1, Yuko Tadokoro1, Takako Ooshio1,2, Yukio Kondo3, Shinji Nakao3, Noboru Motoyama4 & Atsushi Hirao1,2

  1. Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
  2. Core Research for Evolution Science and Technology (CREST), Japan Science and Technology Agency (JST), Chiyoda-ku, Tokyo 102-0075, Japan
  3. Cellular Transplantation Biology, Division of Cancer Medicine, Kanazawa University, Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan
  4. Department of Geriatric Medicine, National Institute for Longevity Sciences, National Center for Gerontology and Geriatrics, Obu, Aichi 474-8522, Japan
  5. These authors contributed equally to this work.

Correspondence to: Kazuhito Naka1,5Atsushi Hirao1,2 Correspondence and requests for materials should be addressed to K.N. (Email: kazunaka@kenroku.kanazawa-u.ac.jp) or A.H. (Email: ahirao@kenroku.kanazawa-u.ac.jp).

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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