دورية أكاديمية
أعرض في EDS

ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy.

التفاصيل البيبلوغرافية
العنوان: ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy.
المؤلفون: Ianniciello A; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Zarou MM; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Rattigan KM; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Scott M; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Dawson A; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Dunn K; Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0ZD, UK., Brabcova Z; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Kalkman ER; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Nixon C; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK., Michie AM; Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0ZD, UK., Copland M; Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0ZD, UK., Vetrie D; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK., Ambler M; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK., Saxty B; LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK., Helgason GV; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
المصدر: Science translational medicine [Sci Transl Med] 2021 Sep 29; Vol. 13 (613), pp. eabd5016. Date of Electronic Publication: 2021 Sep 29.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science
مواضيع طبية MeSH: Autophagy* , Oxidative Stress*, Autophagy-Related Protein-1 Homolog/metabolism ; Cell Differentiation ; Stem Cells/metabolism
مستخلص: Inhibition of autophagy has been proposed as a potential therapy for individuals with cancer. However, current lysosomotropic autophagy inhibitors have demonstrated limited efficacy in clinical trials. Therefore, validation of novel specific autophagy inhibitors using robust preclinical models is critical. In chronic myeloid leukemia (CML), minimal residual disease is maintained by persistent leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance and patient relapse. Here, we show that deletion of autophagy-inducing kinase ULK1 (unc-51–like autophagy activating kinase 1) reduces growth of cell line and patient-derived xenografted CML cells in mouse models. Using primitive cells, isolated from individuals with CML, we demonstrate that pharmacological inhibition of ULK1 selectively targets CML LSCs ex vivo and in vivo, when combined with TKI treatment. The enhanced TKI sensitivity after ULK1-mediated autophagy inhibition is driven by increased mitochondrial respiration and loss of quiescence and points to oxidative stress–induced differentiation of CML LSCs, proposing an alternative strategy for treating patients with CML.
التعليقات: Comment in: Autophagy. 2022 Jul;18(7):1734-1736. (PMID: 35227175)
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معلومات مُعتمدة: C55731/A24896 United Kingdom CRUK_ Cancer Research UK; A29754 United Kingdom CRUK_ Cancer Research UK; 29754 United Kingdom CRUK_ Cancer Research UK; MC_PC_18048 United Kingdom MRC_ Medical Research Council; A25142 United Kingdom CRUK_ Cancer Research UK; C57352/A29754 United Kingdom CRUK_ Cancer Research UK
المشرفين على المادة: EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
تواريخ الأحداث: Date Created: 20210929 Date Completed: 20211101 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC7612079
DOI: 10.1126/scitranslmed.abd5016
PMID: 34586834
قاعدة البيانات: MEDLINE
الوصف
تدمد:1946-6242
DOI:10.1126/scitranslmed.abd5016