{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:01:55Z","timestamp":1790946115567,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"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"]}]},{"name":"Canadian Institutes of Health Research","award":["#706288"],"award-info":[{"award-number":["#706288"]}]},{"name":"Canadian Institutes of Health Research","award":["#427201"],"award-info":[{"award-number":["#427201"]}]},{"name":"Canadian Institutes of Health Research","award":["#1LERG904"],"award-info":[{"award-number":["#1LERG904"]}]},{"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"]}]},{"name":"MITACS Accelerate Fellowship","award":["#706288"],"award-info":[{"award-number":["#706288"]}]},{"name":"MITACS Accelerate Fellowship","award":["#427201"],"award-info":[{"award-number":["#427201"]}]},{"name":"MITACS Accelerate Fellowship","award":["#1LERG904"],"award-info":[{"award-number":["#1LERG904"]}]},{"name":"Michael Smith Health Research BC Postdoctoral Trainee Award","award":["#706288"],"award-info":[{"award-number":["#706288"]}]},{"name":"Michael Smith Health Research BC Postdoctoral Trainee Award","award":["#427201"],"award-info":[{"award-number":["#427201"]}]},{"name":"Michael Smith Health Research BC Postdoctoral Trainee Award","award":["#1LERG904"],"award-info":[{"award-number":["#1LERG904"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified miR-185 as a predictive biomarker where reduced expression in CD34+ treatment-na\u00efve CML cells was associated with TKI resistance. We have also identified PAK6 as a target gene of miR-185 that was upregulated in CD34+ TKI-nonresponder cells. However, its role in regulating TKI resistance remains largely unknown. In this study, we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34+ stem\/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy. Interestingly, the genetic and pharmacological suppression of PAK6 significantly reduced proliferation and increased apoptosis in TKI-resistant cells. Cell survivability was further diminished when IM was combined with PAK6 knockdown. Importantly, PAK6 inhibition in TKI-resistant cells induced cell cycle arrest in the G2-M phase and cellular senescence, accompanied by increased levels of DNA damage-associated senescence markers. Mechanically, we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus, PAK6 plays a critical role in determining alternative cell fates in leukemic cells, and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells.<\/jats:p>","DOI":"10.3390\/ijms26136533","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T08:58:23Z","timestamp":1751878703000},"page":"6533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of a PAK6-Mediated MDM2\/p21 Axis That Modulates Survival and Cell Cycle Control of Drug-Resistant Stem\/Progenitor Cells in Chronic Myeloid Leukemia"],"prefix":"10.3390","volume":"26","author":[{"given":"Andrew","family":"Wu","sequence":"first","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada"},{"name":"Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, 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 V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athena","family":"Phoa","sequence":"additional","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zesong","family":"Yang","sequence":"additional","affiliation":[{"name":"Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada"},{"name":"Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna L.","family":"Forrest","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"},{"name":"Leukemia\/Bone Marrow Transplant Program of British Columbia, Vancouver, BC V5Z 1M9, 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 V5Z 1L3, Canada"},{"name":"Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"},{"name":"Department of Medical Genetics, University of British Columbia; Vancouver, BC V6T 1Z4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"ref_1","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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