@article{c86691403c6f49b6858f8e5f971442dc,
title = "Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia",
abstract = "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.",
author = "Lewis, {Alexander C.} and Pope, {Victoria S.} and Tea, {Melinda N.} and Manjun Li and Nwosu, {Gus O.} and Nguyen, {Thao M.} and Wallington-Beddoe, {Craig T.} and Moretti, {Paul A.B.} and Dovile Anderson and Creek, {Darren J.} and Maurizio Costabile and Ali, {Saira R.} and Thompson-Peach, {Chloe A.L.} and Dredge, {B. Kate} and Bert, {Andrew G.} and Goodall, {Gregory J.} and Ekert, {Paul G.} and Brown, {Anna L.} and Richard D'Andrea and Nirmal Robinson and Pitman, {Melissa R.} and Daniel Thomas and Ross, {David M.} and Gliddon, {Briony L.} and Powell, {Jason A.} and Pitson, {Stuart M.}",
note = "Funding Information: This work was supported by a Research Training Program Scholarship and Royal Adelaide Hospital Dawes Top-up scholarship (A.C.L.); the Fay Fuller Foundation, the Royal Adelaide Hospital Research Fund, The Hospital Research Foundation, Senior Research Fellowship GNT1156693 (S.M.P.); Early Career Fellowship PG101400 (T.M.N.); and project grants NT1145139 and GNT1184485 from the National Health and Medical Research Council of Australia. D.T. is supported by the Leukemia and Lymphoma Translation Research Program and a CSL Centenary Fellowship. Funding Information: The authors thank the South Australian Cancer Research Biobank (SACRB) and the patients who donated samples and Sarah Tamang, who provided technical assistance. This work was supported by a Research Training Program Scholarship and Royal Adelaide Hospital Dawes Top-up scholarship (A.C.L.); the Fay Fuller Foundation, the Royal Adelaide Hospital Research Fund, The Hospital Research Foundation, Senior Research Fellowship GNT1156693 (S.M.P.); Early Career Fellowship PG101400 (T.M.N.); and project grants NT1145139 and GNT1184485 from the National Health and Medical Research Council of Australia. D.T. is supported by the Leukemia and Lymphoma Translation Research Program and a CSL Centenary Fellowship. Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",
year = "2022",
month = jun,
day = "30",
doi = "10.1182/blood.2021013277",
language = "English",
volume = "139",
pages = "3737--3751",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "26",
}
