Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
Date
2022
Authors
Lewis, A.C.
Pope, V.S.
Tea, M.N.
Li, M.
Nwosu, G.O.
Nguyen, T.M.
Wallington-Beddoe, C.T.
Moretti, P.A.
Anderson, D.
Creek, D.J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Blood, 2022; 139(26):3737-3751
Statement of Responsibility
Alexander C. Lewis, Victoria S. Pope, Melinda N. Tea, Manjun Li, Gus O. Nwosu, Thao M. Nguyen, Craig T. Wallington-Beddoe, Paul A. B. Moretti, Dovile Anderson, Darren J. Creek, Maurizio Costabile, Saira R. Ali, Chloe A. L. Thompson-Peach, B. Kate Dredge, Andrew G. Bert, Gregory J. Goodall, Paul G. Ekert, Anna L. Brown, Richard D'Andrea, Nirmal Robinson, Melissa R. Pitman, Daniel Thomas, David M. Ross, Briony L. Gliddon, Jason A. Powell, and Stuart M. Pitson
Conference Name
Abstract
Inducing cell death by the sphingolipid ceramide is a potential anti-cancer strategy, but the underlying mechanisms remain poorly defined. Here, we show that triggering accumulation of ceramide in acute myeloid leukaemia (AML) cells by inhibition of sphingosine kinase induces an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This leads to transcription of the BH3-only protein, Noxa, and degradation of the pro-survival Mcl-1 protein on which AML cells are highly dependent on for survival. Targeting this novel ISR pathway in combination with the Bcl-2 inhibitor venetoclax synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anti-cancer effects of ceramide and pre-clinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
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Description
Data source: Supplemental data, https://doi.org/10.1182/blood.2021013277
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Rights
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.