Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Ren, R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nature Rev. Cancer 5, 172–183 (2005)

    Article  CAS  Google Scholar 

  2. Komatsu, N. et al. A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. J. Biol. Chem. 278, 6411–6419 (2003)

    Article  CAS  Google Scholar 

  3. Ghaffari, S., Jagani, Z., Kitidis, C., Lodish, H. F. & Khosravi-Far, R. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc. Natl Acad. Sci. USA 100, 6523–6528 (2003)

    Article  ADS  CAS  Google Scholar 

  4. Essafi, A. et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24, 2317–2329 (2005)

    Article  CAS  Google Scholar 

  5. Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro . Blood 99, 319–325 (2002)

    Article  CAS  Google Scholar 

  6. Michor, F. et al. Dynamics of chronic myeloid leukaemia. Nature 435, 1267–1270 (2005)

    Article  ADS  CAS  Google Scholar 

  7. Roeder, I. et al. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nature Med. 12, 1181–1184 (2006)

    Article  CAS  Google Scholar 

  8. Jørgensen, H. G., Allan, E. K., Jordanides, N. E., Mountford, J. C. & Holyoake, T. L. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109, 4016–4019 (2007)

    Article  Google Scholar 

  9. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210 bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990)

    Article  ADS  CAS  Google Scholar 

  10. Hu, Y. et al. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc. Natl Acad. Sci. USA 103, 16870–16875 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Neering, S. J. et al. Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 110, 2578–2585 (2007)

    Article  CAS  Google Scholar 

  12. Ito, K. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072–1078 (2008)

    Article  ADS  CAS  Google Scholar 

  13. Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009)

    Article  ADS  CAS  Google Scholar 

  14. Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007)

    Article  CAS  Google Scholar 

  15. Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1, 101–112 (2007)

    Article  CAS  Google Scholar 

  16. Yalcin, S. et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J. Biol. Chem. 283, 25692–25705 (2008)

    Article  CAS  Google Scholar 

  17. Yamazaki, S. et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 25, 3515–3523 (2006)

    Article  CAS  Google Scholar 

  18. Pear, W. S. et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92, 3780–3792 (1998)

    CAS  PubMed  Google Scholar 

  19. Yamazaki, S. et al. TGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 113, 1250–1256 (2009)

    Article  CAS  Google Scholar 

  20. Massagué, J. TGFβ in Cancer. Cell 134, 215–230 (2008)

    Article  Google Scholar 

  21. Sawyer, J. S. et al. Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. J. Med. Chem. 46, 3953–3956 (2003)

    Article  CAS  Google Scholar 

  22. Bhaskar, P. T. & Hay, N. The two TORCs and Akt. Dev. Cell 12, 487–502 (2007)

    Article  CAS  Google Scholar 

  23. Kodama, H., Nose, M., Niida, S. & Nishikawa, S. Involvement of the c-kit receptor in the adhesion of hematopoietic stem cells to stromal cells. Exp. Hematol. 22, 979–984 (1994)

    CAS  PubMed  Google Scholar 

  24. Møller, G. M., Frost, V., Melo, J. V. & Chantry, A. Upregulation of the TGFβ signalling pathway by Bcr-Abl: implications for haemopoietic cell growth and chronic myeloid leukaemia. FEBS Lett. 581, 1329–1334 (2007)

    Article  Google Scholar 

  25. Pellicano, F. et al. FOXO transcription factor activity is partially retained in quiescent CML stem cells and induced by tyrosine kinase inhibitors in CML progenitor cells. Blood 10.1182/blood-2009-06-226621 (1 December 2009)

  26. Ema, H. et al. Adult mouse hematopoietic stem cells: purification and single-cell assays. Nature Protocols 1, 2979–2987 (2006)

    Article  CAS  Google Scholar 

  27. Bouchard, C. et al. FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev. 21, 2775–2787 (2007)

    Article  CAS  Google Scholar 

  28. Dash, A. B. et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc. Natl Acad. Sci. USA 99, 7622–7627 (2002)

    Article  ADS  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. Kazuhito Naka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takayuki Hoshii
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teruyuki Muraguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuko Tadokoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takako Ooshio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yukio Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shinji Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Noboru Motoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Atsushi Hirao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kazuhito Naka or Atsushi Hirao.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-25 with Legends, Supplementary Discussions and Supplementary References. (PDF 10769 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08734

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing