{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:20:29Z","timestamp":1790742029558,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canadian Cancer Society","award":["706288"],"award-info":[{"award-number":["706288"]}]},{"name":"Canadian Cancer Society","award":["427201"],"award-info":[{"award-number":["427201"]}]},{"name":"Canadian Cancer Society","award":["1LERG904"],"award-info":[{"award-number":["1LERG904"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["706288"],"award-info":[{"award-number":["706288"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["427201"],"award-info":[{"award-number":["427201"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["1LERG904"],"award-info":[{"award-number":["1LERG904"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Collings Stevens Chronic Leukemia Research Fund","award":["706288"],"award-info":[{"award-number":["706288"]}]},{"name":"Collings Stevens Chronic Leukemia Research Fund","award":["427201"],"award-info":[{"award-number":["427201"]}]},{"name":"Collings Stevens Chronic Leukemia Research Fund","award":["1LERG904"],"award-info":[{"award-number":["1LERG904"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. In particular, patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs), partly due to a persistent population of TKI-resistant leukemic stem cells (LSCs). Therefore, identifying specific pathways crucial for LSC maintenance is necessary. The Hedgehog (HH) pathway, especially the protein Smoothened (SMO), has been found to be essential for CML LSCs, but its role in TKI resistance is still largely unknown. We have now demonstrated that the expression of HH pathway genes SMO and GLI2 is increased in CD34+ CML stem\/progenitor cells compared to healthy counterparts, and is higher in TKI-nonresponders than in responders by transcriptome profiling and qRT-PCR analysis. Interestingly, they are most highly expressed in LSCs compared to progenitors and mature cells in TKI-nonresponders. Inhibition of SMO through genetic knockdown or with a potent, selective SMO inhibitor, Glasdegib, reduces the survival of cells from nonresponder patients. Notably, SMO inhibition also sensitizes TKI-nonresponder stem\/progenitor cells to Bostutinib, a second-generation TKI, both in vitro and in a patient-derived xenotransplantation (PDX) model. These findings present a promising therapeutic target and a model for curative combination therapies in stem-cell-driven cancers.<\/jats:p>","DOI":"10.3390\/cells14191565","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T09:41:02Z","timestamp":1760002862000},"page":"1565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dual Targeting of Smoothened, a Key Regulator in the Hedgehog Pathway, and BCR-ABL1 Effectively Eradicates Drug-Insensitive Stem\/Progenitor Cells in Chronic Myeloid Leukemia"],"prefix":"10.3390","volume":"14","author":[{"given":"Kelly A.","family":"Turner","sequence":"first","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V6T 1Z3, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Rothe","sequence":"additional","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V6T 1Z3, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna L.","family":"Forrest","sequence":"additional","affiliation":[{"name":"Leukemia\/Bone Marrow Transplant Program of British Columbia, Vancouver, BC V6T 1Z3, Canada"},{"name":"Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8974-7340","authenticated-orcid":false,"given":"Xiaoyan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V6T 1Z3, Canada"},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"},{"name":"Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/243290a0","article-title":"Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining","volume":"243","author":"Rowley","year":"1973","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1056\/NEJM199904293401706","article-title":"Chronic myeloid leukemia","volume":"340","author":"Sawyers","year":"1999","journal-title":"N. 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