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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\u2013mediated 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.<\/jats:p>","DOI":"10.1182\/blood.2021013277","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T18:52:04Z","timestamp":1650480724000},"page":"3737-3751","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":52,"title":["Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia"],"prefix":"10.1182","volume":"139","author":[{"given":"Alexander C.","family":"Lewis","sequence":"first","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria S.","family":"Pope","sequence":"additional","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7045-1198","authenticated-orcid":false,"given":"Melinda N.","family":"Tea","sequence":"additional","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjun","family":"Li","sequence":"additional","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gus O.","family":"Nwosu","sequence":"additional","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thao M.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"},{"name":"2Faculty of Health Sciences, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7457-5937","authenticated-orcid":false,"given":"Craig T.","family":"Wallington-Beddoe","sequence":"additional","affiliation":[{"name":"1Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia;"},{"name":"2Faculty of Health Sciences, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia;"},{"name":"3College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia;"},{"name":"4Flinders Medical Centre, Bedford Park, SA, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A. 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