CERAMIDE EVOKES AN APOPTOTIC INTEGRATED STRESS RESPONSE IN ACUTE MYELOID LEUKEMIA

• Published in: Experimental hematology 2019-08, Vol.76, p.S83-S83
• Main Authors: Powell, Jason, Lewis, Alexander, Tea, Melinda, Nguyen, Thao, Wallington-Beddoe, Craig, Anderson, Dovile, Creek, Darren, D'Andrea, Richard, Ross, David, Thomas, Daniel, Pitson, Stuart
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2019.06.424

Increases in the pro-apoptotic lipid ceramide are thought to contribute to the efficacy of many anti-cancer agents used in the clinic. How the tumour suppressive activity of ceramide is exerted, however, remains poorly understood. Sphingosine kinase 1 (SPHK1) is a promoter of oncogenic signalling by the production of sphingosine-1-phosphate at the expense of pro-apoptotic lipids, ceramide and sphingosine. We report that SPHK1 inhibition in acute myeloid leukaemia (AML) cells results in ceramide accumulation which evokes an apoptotic integrated stress response (ISR). Specifically, ceramide activates protein kinase R (PKR) which phosphorylates eIF2a to induce ATF4-dependant transcriptional upregulation of the BH3 only protein Noxa. These increases in Noxa results in its binding to Mcl-1, facilitating Mcl-1 degradation, and sensitising AML cells to the clinically approved Bcl-2 inhibitor venetoclax. Using the Beat AML master trial, a multi-centre clinical trial integrating genomics data with clinical decisions for the addition of targeted agents based on a patients mutations, we identified patients with a K-Ras, PTPN11 and SF3B1 mutations to confer venetoclax resistance. Excitingly, we showed that combination of SPHK1 inhibitors and venetoclax was effective in these resistant cell lines, primary AML blasts, purified leukemic initiating cells LICs and reduced leukemic burden in an orthotopic patient derived xenograft model. These studies provide novel insight of how ceramides induce ISR activation and the sensitisation of AML patients to venetoclax treatment.