Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.

Alexander C. Lewis, Victoria Pope, Melinda N. Tea, Manjun Li, Gus O. Nwosu, Thao M. Nguyen, Associate Professor Craig T. Wallington-Beddoe, Paul A. Moretti, Dovile Anderson, Darren J. Creek, Maurizio Costabile, Saira R. Ali, Chloe AL. Thompson-Peach, B. Dredge, Andrew G. Bert, Gregory J. Goodall, Paul G. Eckert, Anna L. Brown, Richard J. D'Andrea, Nirmal RobinsonMelissa R. Pitman, Daniel Thomas, David Ross, Briony L. Gliddon, Jason A. Powell, Stuart M. Pitson

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Number of pages33
JournalBlood
Early online date20 Apr 2022
DOIs
Publication statusE-pub ahead of print - 20 Apr 2022

Keywords

  • Acute Myeloid Leukemia
  • Ceramide
  • Bcl-2 inhibitor resistance

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