JOM KITA KE POLITEKNIK

ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy (Record no. 273)

MARC details
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Personal name Ianniciello, Angela
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9 (RLIN) 1022
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Title ULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy
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Date of publication, distribution, etc. 2021-09-29.
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General note /pmc/articles/PMC7612079/
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General note /pubmed/34586834
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Summary, etc. 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.
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Terms governing use and reproduction
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Terms governing use and reproduction exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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Language note en
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Topical term or geographic name as entry element Article
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Genre/form data or focus term Text
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Personal name Zarou, Martha M.
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9 (RLIN) 1023
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Personal name Rattigan, Kevin M.
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9 (RLIN) 1024
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Personal name Scott, Mary
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9 (RLIN) 1025
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Personal name Dawson, Amy
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9 (RLIN) 1026
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Personal name Dunn, Karen
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9 (RLIN) 1027
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Personal name Brabcova, Zuzana
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9 (RLIN) 1028
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Personal name Kalkman, Eric R.
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9 (RLIN) 1029
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Personal name Nixon, Colin
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9 (RLIN) 1030
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Personal name Michie, Alison M.
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9 (RLIN) 1031
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Personal name Copland, Mhairi
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9 (RLIN) 1032
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Personal name Vetrie, David
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9 (RLIN) 1033
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Personal name Ambler, Martin
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9 (RLIN) 1034
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Personal name Saxty, Barbara
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9 (RLIN) 1035
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Personal name Helgason, G. Vignir
Relator term author
9 (RLIN) 1036
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Note Sci Transl Med
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Uniform Resource Identifier <a href="http://dx.doi.org/10.1126/scitranslmed.abd5016">http://dx.doi.org/10.1126/scitranslmed.abd5016</a>
Public note Connect to this object online.

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