Ianniciello, A. et al. (2021) ULK1 inhibition promotes oxidative stress–induced differentiation and sensitizes leukemic stem cells to targeted therapy. Science Translational Medicine, 13(613), eabd5016. (doi: 10.1126/scitranslmed.abd5016) (PMID:34586834)
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252673.pdf - Accepted Version 18MB |
Abstract
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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Scott, Dr Mary and Vetrie, Professor David and Copland, Professor Mhairi and Ianniciello, Ms Angela and Dawson, Ms Amy and Rattigan, Dr Kevin and Michie, Professor Alison and Kalkman, Dr Eric and Nixon, Mr Colin and Dunn, Mrs Karen and Brabcova, Dr Zuzana and Zarou, Martha-Maria and Helgason, Professor Vignir |
| Authors: | Ianniciello, A., Zarou, M. M., Rattigan, K. M., Scott, M., Dawson, A., Dunn, K., Brabcova, Z., Kalkman, E. R., Nixon, C., Michie, A. M., Copland, M., Vetrie, D., Ambler, M., Saxty, B., and Helgason, G. V. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Science Translational Medicine |
| Publisher: | American Association for the Advancement of Science |
| ISSN: | 1946-6234 |
| ISSN (Online): | 1946-6242 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in Science Translational Medicine 13(613): eabd5016 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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