Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia (original) (raw)

• Letter
• Published: 25 January 2009
• Alan Chen1 na1,
• Catriona H. Jamieson3,
• Mark Fereshteh1,
• Annelie Abrahamsson3,
• Jordan Blum1,
• Hyog Young Kwon1,
• Jynho Kim4,
• John P. Chute2,
• David Rizzieri2,
• Michael Munchhof5,
• Todd VanArsdale6,
• Philip A. Beachy4 &
• …
• Tannishtha Reya1

Nature volume 458, pages 776–779 (2009)Cite this article

• 5845 Accesses
• 702 Citations
• 19 Altmetric
• Metrics details

A Corrigendum to this article was published on 30 July 2009

Abstract

Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established1, its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these functions to cancer development has not been determined. Here we show that the loss of Smoothened (Smo), an essential component of the Hh pathway2, impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR–ABL1 oncoprotein3. Loss of Smo causes depletion of CML stem cells—the cells that propagate the leukaemia—whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wild-type BCR–ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML4,5 might be avoided by targeting this essential stem cell maintenance pathway.

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

Access options

Additional access options:

• Log in
• Learn about institutional subscriptions
• Read our FAQs
• Contact customer support

Similar content being viewed by others

References

1. Ingham, P. W. & Placzek, M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nature Rev. Genet. 7, 841–850 (2006)
   Article CAS PubMed Google Scholar
2. Rohatgi, R. & Scott, M. P. Patching the gaps in Hedgehog signalling. Nature Cell Biol. 9, 1005–1009 (2007)
   Article CAS PubMed Google Scholar
3. Ren, R. Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nature Rev. Cancer 5, 172–183 (2005)
   Article CAS Google Scholar
4. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001)
   Article CAS PubMed 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 PubMed Google Scholar
6. 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 PubMed PubMed Central Google Scholar
7. Jorgensen, 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 CAS PubMed Google Scholar
8. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)
   Article ADS CAS PubMed Google Scholar
9. Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001)
   Article ADS CAS PubMed Google Scholar
10. Evangelista, M., Tian, H. & de Sauvage, F. J. The hedgehog signaling pathway in cancer. Clin. Cancer Res. 12, 5924–5928 (2006)
    Article CAS PubMed Google Scholar
11. Long, F., Zhang, X. M., Karp, S., Yang, Y. & McMahon, A. P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099–5108 (2001)
    CAS PubMed Google Scholar
12. Zhao, C. et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo . Cancer Cell 12, 528–541 (2007)
    Article CAS PubMed PubMed Central Google Scholar
13. 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 PubMed Google Scholar
14. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171–10178 (2006)
    Article CAS PubMed PubMed Central Google Scholar
15. Wu, M. et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541–554 (2007)
    Article CAS PubMed PubMed Central Google Scholar
16. Chen, J. K., Taipale, J., Cooper, M. K. & Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 16, 2743–2748 (2002)
    Article CAS PubMed PubMed Central Google Scholar
17. Thayer, S. P. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425, 851–856 (2003)
    Article ADS CAS PubMed PubMed Central Google Scholar
18. Watkins, D. N. et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003)
    Article ADS CAS PubMed Google Scholar
19. O’Hare, T., Corbin, A. S. & Druker, B. J. Targeted CML therapy: controlling drug resistance, seeking cure. Curr. Opin. Genet. Dev. 16, 92–99 (2006)
    Article PubMed Google Scholar
20. Azam, M., Latek, R. R. & Daley, G. Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL . Cell 112, 831–843 (2003)
    Article CAS PubMed Google Scholar
21. Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172–180 (2001)
    Article CAS Google Scholar
22. Balordi, F. & Fishell, G. Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J. Neurosci. 27, 14248–14259 (2007)
    Article CAS PubMed PubMed Central Google Scholar
23. Han, Y. G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nature Neurosci. 11, 277–284 (2008)
    Article CAS PubMed Google Scholar
24. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997)
    Article CAS PubMed Google Scholar
25. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996)
    Article ADS CAS PubMed Google Scholar
26. Dierks, C. et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nature Med. 13, 944–951 (2007)
    Article CAS PubMed Google Scholar
27. Peacock, C. D. et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl Acad. Sci. USA 104, 4048–4053 (2007)
    Article ADS CAS PubMed PubMed Central Google Scholar
28. Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L. & Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 317, 337 (2007)
    Article ADS CAS PubMed Google Scholar
29. Kennedy, J. A., Barabe, F., Poeppl, A. G., Wang, J. C. & Dick, J. E. Comment on “Tumor growth need not be driven by rare cancer stem cells”. Science 318 1722 10.1126/science.1149590 (2007)
    Article ADS CAS PubMed Google Scholar
30. Adams, J. M., Kelly, P. N., Dakic, A., Nutt, S. L. & Strasser, A. Reply. Science 318 1722 10.1126/science.1149672 (2007)
    Article ADS CAS Google Scholar

Download references

Acknowledgements

We wish to thank R. Wechsler-Reya for critical advice, D. Kioussis for Vav-Cre transgenic mice, A. M. Pendergast, A. Means and B. Hogan for review of the manuscript, S. Li for advice on mouse CML experiments, G. Daley, M. Azam and S. Li for the T315I BCR–ABL1 construct, B. Harvat for cell sorting, and J. Harris, B. Zimdahl, N. D’Amato and S. Honeycutt for experimental help. T.R. is a recipient of a CRI Investigator Award, an EMF New Scholar award and a Leukemia and Lymphoma Society Scholar Award, M.F. is supported by the Duke Molecular Cancer Biology Training grant and C.H.J. is funded by the California Institute of Regenerative Medicine and a sponsored research agreement with Pfizer. This work was also supported by National Institutes of Health grants DK63031, DK072234, AI067798 and the Lisa Stafford Memorial Prize to T.R.

Author information

Author notes

1. Chen Zhao and Alan Chen: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Pharmacology and Cancer Biology,,
   Chen Zhao, Alan Chen, Mark Fereshteh, Jordan Blum, Hyog Young Kwon & Tannishtha Reya
2. Department of Medicine, Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina 27710, USA,
   John P. Chute & David Rizzieri
3. Department of Medicine, Stem Cell Research Program, Moores UCSD Cancer Center La Jolla, California 92093, USA,
   Catriona H. Jamieson & Annelie Abrahamsson
4. Department of Developmental Biology Institute of Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, California 94305, USA,
   Jynho Kim & Philip A. Beachy
5. Division of Medicinal Chemistry, Pfizer Laboratories, Groton, Connecticut 06340, USA,
   Michael Munchhof
6. Division of Oncology, Pfizer Laboratories, La Jolla, California 92121, USA,
   Todd VanArsdale

Authors

1. Chen Zhao
   You can also search for this author inPubMed Google Scholar
2. Alan Chen
   You can also search for this author inPubMed Google Scholar
3. Catriona H. Jamieson
   You can also search for this author inPubMed Google Scholar
4. Mark Fereshteh
   You can also search for this author inPubMed Google Scholar
5. Annelie Abrahamsson
   You can also search for this author inPubMed Google Scholar
6. Jordan Blum
   You can also search for this author inPubMed Google Scholar
7. Hyog Young Kwon
   You can also search for this author inPubMed Google Scholar
8. Jynho Kim
   You can also search for this author inPubMed Google Scholar
9. John P. Chute
   You can also search for this author inPubMed Google Scholar
10. David Rizzieri
    You can also search for this author inPubMed Google Scholar
11. Michael Munchhof
    You can also search for this author inPubMed Google Scholar
12. Todd VanArsdale
    You can also search for this author inPubMed Google Scholar
13. Philip A. Beachy
    You can also search for this author inPubMed Google Scholar
14. Tannishtha Reya
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toTannishtha Reya.

Ethics declarations

Competing interests

[Competing Interests: C.H.J. receives research support from Pfizer Inc., and is a consultant for Wintherix. T.V.A. and M.M. are employed by Pfizer Inc. D.R. receives research support from Novartis, Bristol Myers Squibb and Ariad. P.A.B. is a consultant for Fate Therapeutics and holds stock options or stock in Fate and Curis.]

Supplementary information

PowerPoint slides

Rights and permissions

About this article

Cite this article

Zhao, C., Chen, A., Jamieson, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.Nature 458, 776–779 (2009). https://doi.org/10.1038/nature07737

Download citation

• Received: 10 June 2008
• Accepted: 18 December 2008
• Published: 25 January 2009
• Issue Date: 09 April 2009
• DOI: https://doi.org/10.1038/nature07737

This article is cited by

Editorial Summary

Hedgehog maintains cancer stem cells

Hedgehog signalling has been implicated in a number of cancers. It is now shown to be important in chronic myeloid leukaemias (CML) where it acts to maintain leukaemia stem cells, by regulating the expression of Numb. Importantly, CML stem cells can be depleted when Hedgehog signalling is inhibited, including cells that are resistant to the drug imatinib that is used to treat CML.