Pb1793: mcl-1 inhibition affects lipidome which may be linked to tumor immunity and cancer-related inflammation in acute myeloid leukemia

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Myeloid cell leukemia-1 (Mcl-1), an inhibitor of apoptosis, is overexpressed in acute myeloid leukemia (AML). Despite the availability of numerous treatments in clinical settings, efficient approaches are still needed for the treatment of AML. Small molecule inhibitor, S63845, specifically binds to Mcl-1 and inhibits cell proliferation in AML cells. However, the exact mechanism of S63845 in AML cells remains unknown. Tumor cells have been found to have altered lipid compositions, which can impact their response to various agents. Bioactive sphingolipids play a crucial role in various cellular processes. Sphingolipid signaling pathways are important in tumor immunology by controlling the anti-tumor abilities of immune cells. Sphingosine-1-P triggers pro-inflammatory signals, while the inhibition of sphingosine kinase-1 activity leads to a reduction of sphingosine-1-P, resulting in enhanced efficiency of immunotherapy. Despite of some studies on the effects of Mcl-1 on inflammation, little is known about the effects on tumor immunity and cancer-related inflammation. Aims: The goal of this study was to investigate the impact of the Mcl-1 inhibitor, S63845, on lipid profiles in AML cell lines with a specific emphasis on sphingolipids, and to explore its effects on the expression levels of the genes involved in tumor immunity and cancer-related inflammation as well as to propose a link between the Mcl-1, sphingolipids, and tumor immunity. Methods: The cytotoxicity of S63845 was determined in three different AML cell lines (MV4-11, HL60, KG1) by MTT cell proliferation assay. The lipidome was analyzed by quantitative shotgun lipidomics, which analyzed 378 individual lipid species from 26 classes in the major lipid categories. The differential expression data from GEO datasets through NCBI were analyzed by GEO2R to compare the expression levels of MCL1, ceramide synthase (CERS) genes and the genes involved in tumor immunity and cancer-related inflammation from PBMC samples of AML patients and healthy individuals. Results: The IC50 values for S63845 were determined to be 7 nM for MV4-11, 53 nM for HL60, and 479 nM for KG1 cell lines. The lipidome results showed that S63845 treatment caused an increase in ceramide (Cer) levels in MV4-11 and KG1, while reducing downstream sphingolipids. Conversely, in HL60 cell lines, S63845 treatment led to an increase in hexosylceramide (HexCer) levels, with decreases in Cer and sphingomyelin (SM). Analysis of GEO datasets revealed that expression levels of MCL1, and the genes including IL10, LAMP3, and RGS1, related to the activation of cancer-related inflammation, are higher in AML patient samples as compared to the healthy individuals. However, expression levels of CERS1 and CERS2 genes, and the genes including TICAM1, TICAM2, SOCS7, and CD53, related to the activation of tumor immunity, are found lower in AML patient samples. Summary/Conclusion: The findings of this study suggest that S63845 may reduce cell proliferation by modulating the lipid compositions, especially, by increasing ceramide levels in AML cell lines. Additionally, the study highlights that S63845 has a distinct impact on the lipid profiles of different AML cell lines, indicating the potential of using lipidomic profiles as markers. Importantly, our study proposes that the increases in Cer levels in response to S63845 treatment may occur due to SM hydrolysis and may be linked to the anti-inflammatory effects of S63845 in AML cell lines, which deserve further investigation to fully understand the specific mechanisms. Keywords: Mcl-1, Acute promyelocytic leukemia, Lipid metabolism, Acute myeloid leukemia