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We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34<jats:sup>+<\/jats:sup> CP-CML stem\/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34<jats:sup>+<\/jats:sup> CP-CML cells, reducing the number and self-renewal capacity of CML LSC <jats:italic>in vitro<\/jats:italic>. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225\u2009+\u2009nilotinib reduced CD34<jats:sup>+<\/jats:sup> CP-CML cell engraftment in NSG mice and, upon administration to EGFP<jats:sup>+<\/jats:sup> \/SCLtTA\/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells.<\/jats:p>","DOI":"10.1038\/srep25476","type":"journal-article","created":{"date-parts":[[2016,5,9]],"date-time":"2016-05-09T09:10:16Z","timestamp":1462785016000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia"],"prefix":"10.1038","volume":"6","author":[{"given":"David A.","family":"Irvine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Kinstrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Tarafdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria L.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hothri A.","family":"Moka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinwei","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Nixon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W.","family":"Manley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Wheadon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Goodlad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa L.","family":"Holyoake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mhairi","family":"Copland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,9]]},"reference":[{"key":"BFsrep25476_CR1","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/S0140-6736(13)62120-0","volume":"385","author":"JF Apperley","year":"2015","unstructured":"Apperley, J. 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TLH has received research funding from Novartis and Bristol-Myers Squibb, is an advisory board member for Novartis and Ariad and has received honoraria from Bristol-Myers Squibb, Novartis and Ariad. RB has received research funding from Novartis, has been an advisory board member and has received honoraria from Novartis, Bristol-Myers Squibb and Teva. MC has received research funding from Novartis and Bristol-Myers Squibb, is an advisory board member for Bristol-Myers Squibb, Novartis, Ariad and Pfizer and has received honoraria from Bristol-Myers Squibb, Novartis, Ariad and Pfizer. The other authors have no additional financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"25476"}}