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
department or school: Medicine, Faculty of
department or school: Non UBC
department or school: Medical Genetics, Department of
department or school: Medicine, Department of
data provider: DSpace
identifier citation: International Journal of Molecular Sciences 26 (13): 6533 (2025)
contributor: BC Cancer Research Centre. Terry Fox Laboratory
contributor: Leukemia/Bone Marrow Transplant Program of British Columbia
creator: Wu, Andrew
creator: Chen, Min
creator: Phoa, Athena
creator: Yang, Zesong
creator: Forrest, Donna L.
creator: Jiang, Xiaoyan
issued: 2025-07-25T13:46:25Z
issued: 2025-07-07
description: 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.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/91696
note: Academic Editor: Alessandro PoggiReceived: 6 June 2025Revised: 28 June 2025Accepted: 4 July 2025Published: 7 July 2025Citation: Wu, A.; Chen, M.; Phoa, A.;Yang, Z.; Forrest, D.L.; Jiang, X.Identification of a PAK6-MediatedMDM2/p21 Axis That ModulatesSurvival and Cell Cycle Control ofDrug-Resistant Stem/Progenitor Cellsin Chronic Myeloid Leukemia. Int. J.Mol. Sci. 2025, 26, 6533. https://doi.org/10.3390/ijms26136533Copyright: © 2025 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license(https://creativecommons.org/licenses/by/4.0/).ArticleIdentification of a PAK6-Mediated MDM2/p21 Axis ThatModulates Survival and Cell Cycle Control of Drug-ResistantStem/Progenitor Cells in Chronic Myeloid LeukemiaAndrew Wu 1,2, Min Chen 1, Athena Phoa 1, Zesong Yang 1,3, Donna L. Forrest 2,4 and Xiaoyan Jiang 1,2,5,*1 Collings Stevens Chronic Leukemia Research Laboratory, Terry Fox Laboratory, British Columbia CancerResearch Institute, Vancouver, BC V5Z 1L3, Canada; mchen@bccrc.ca (M.C.)2 Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada3 Department of Hematology, The First Affiliated Hospital of Chongqing Medical University,Chongqing 400000, China4 Leukemia/Bone Marrow Transplant Program of British Columbia, Vancouver, BC V5Z 1M9, Canada5 Department of Medical Genetics, University of British Columbia; Vancouver, BC V6T 1Z4, Canada* Correspondence: xjiang@bccrc.caAbstractChronic myeloid leukemia (CML) is a leading example of a malignancy where a moleculartargeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosinekinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We haverecently identified miR-185 as a predictive biomarker where reduced expression in CD34+treatment-naïve CML cells was associated with TKI resistance. We have also identifiedPAK6 as a target gene of m…
has type: Article
is shown at: 10.14288/1.0449492
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: Multidisciplinary Digital Publishing Institute
publisher DOI: 10.3390/ijms26136533
rights: CC BY 4.0
rights URI: https://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
scholar level: Researcher
subject: CML
subject: leukemic stem cells
subject: TKI therapy
subject: TKI resistance
subject: cell cycle
subject: Imatinib
subject: PAK6
subject: small molecule inhibitors
subject: senescence
subject: DNA damage
type: Text
identifier URI: http://hdl.handle.net/2429/91696