1. Department of Pharmacology and Cancer Biology,
2. Department of Medicine, Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina 27710, USA
3. Department of Medicine, Stem Cell Research Program, Moores UCSD Cancer Center La Jolla, California 92093, USA
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
5. Division of Medicinal Chemistry, Pfizer Laboratories, Groton, Connecticut 06340, USA
6. Division of Oncology, Pfizer Laboratories, La Jolla, California 92121, USA
7. These authors contributed equally to this work.

Correspondence to: Tannishtha Reya¹ Correspondence and requests for materials should be addressed to T.R. (Email: t.reya@duke.edu).

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 CML^{4, 5} might be avoided by targeting this essential stem cell maintenance pathway.

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