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.
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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.
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[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.]
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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
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DOI: https://doi.org/10.1038/nature07737
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