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

Lewis, AC; Pope, VS; Tea, MN; Li, M; Nwosu, GO; Nguyen, TM; Wallington-Beddoe, CT; Moretti, PAB; Anderson, D; Creek, DJ; Costabile, M; Ali, SR; Thompson-Peach, CAL; Dredge, BK; Bert, AG; Goodall, GJ; Ekert, PG; Brown, AL; D&#39;Andrea, R; Robinson, N; Pitman, MR; Thomas, D; Ross, DM; Gliddon, BL; Powell, JA; Pitson, SM

Author(s): Lewis, AC; Pope, VS; Tea, MN; Li, M; Nwosu, GO; Nguyen, TM; Wallington-Beddoe, CT; Moretti, PAB; Anderson, D; Creek, DJ; Costabile, M; Ali, SR; Thompson-Peach, CAL; Dredge, BK; Bert, AG; Goodall, GJ; Ekert, PG; Brown, AL; D'Andrea, R; Robinson, N; Pitman, MR; Thomas, D; Ross, DM; Gliddon, BL; Powell, JA; Pitson, SM;
Details: Publication Year 2022-06-30,Volume 139,Issue #26,Page 3737-3751
Journal Title: Blood
Publication Type: Research article
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.
Keywords: *Antineoplastic Agents/therapeutic use; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use; Cell Line, Tumor; Ceramides/pharmacology; Humans; *Leukemia, Myeloid, Acute/drug therapy/genetics/metabolism; Myeloid Cell Leukemia Sequence 1 Protein/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism
Department(s): Laboratory Research
PubMed ID: 35443029
Publisher's Version: https://doi.org/10.1182/blood.2021013277
Open Access at Publisher's Site: https://doi.org/10.1182/blood.2021013277
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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