Blood · 2022
Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Lewis Alexander C, Pope Victoria S, Tea Melinda N, Li Manjun, Nwosu Gus O, Nguyen Thao M, Wallington-Beddoe Craig T, Moretti Paul A B, Anderson Dovile, Creek Darren J, Costabile Maurizio, Ali Saira R, Thompson-Peach Chloe A L, Dredge B Kate, Bert Andrew G, Goodall Gregory J, Ekert Paul G, Brown Anna L, D'Andrea Richard, Robinson Nirmal, Pitman Melissa R, Thomas Daniel, Ross David M, Gliddon Briony L, Powell Jason A, Pitson Stuart M
Аннотация
Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent 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 anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.