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
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Le résumé fourni par la source
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-naïve 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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- 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
- Date Crossref
- 07/07/2025
- Éditeur
- MDPI AG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of British Columbia Department of Medicine pays non établi dans la noticeUniversité ou école supérieure
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Terry Fox Research Institute pays non établi dans la noticeStructure de recherche
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The Affiliated Yongchuan Hospital of Chongqing Medical University pays non établi dans la noticeÉtablissement de santé
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Leukemia & Lymphoma Society of Canada pays non établi dans la noticeInstitution
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Collings Stevens Chronic Leukemia Research Laboratory pays non établi dans la noticeStructure de recherche
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The First Affiliated Hospital of Chongqing Medical University Department of Hematology pays non établi dans la noticeUniversité ou école supérieure
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Leukemia/Bone Marrow Transplant Program of British Columbia pays non établi dans la noticeInstitution
Department of Medicine — University of British Columbia, Terry Fox Research Institute et The Affiliated Yongchuan Hospital of Chongqing Medical University, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.