Journal
BLOOD
Volume 139, Issue 26, Pages 3737-3751Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021013277
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Funding
- Research Training Program Scholarship
- Royal Adelaide Hospital Dawes Top-up scholarship
- Fay Fuller Foundation
- Royal Adelaide Hospital Research Fund
- Hospital Research Foundation
- National Health and Medical Research Council of Australia [GNT1156693, PG101400, NT1145139, GNT1184485]
- Leukemia and Lymphoma Translation Research Program
- CSL Centenary Fellowship
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In this study, the accumulation of ceramide in AML cells induced an apoptotic integrated stress response through the activation of transcription factor ATF4. This response led to the degradation of the prosurvival protein Mcl-1, resulting in cell death. Combination treatment with the Bcl-2 inhibitor venetoclax synergistically killed AML cells and reduced leukemic stem cells.
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.
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