Abstract Objectives: Tyrosine kinase inhibitor (TKI) resistance is one of the major obstacles in chronic myeloid leukemia (CML) treatment. Ceramide, the central molecule of the sphingolipid metabolism, is synthesized by ceramide synthases (CERS1-6). While ceramide is known to be a pro-apoptotic molecule, glucosylceramide and sphingosine 1-phosphate converted from the ceramide are anti-apoptotic. In this study, we aimed to determine the potential roles of bioactive sphingolipids in terms of predicting drug resistance and prognosis in chronic myeloid leukemia patient samples. Materials and methods: Expression levels of CERS1-6, GCS, SK1, and BCR/ABL genes of 66 CML patients that are newly diagnosed, TKI-resistant or TKI-sensitive were analyzed by qRT-PCR. Results: CERS1-6 genes were expressed higher in the patients treated with TKIs than that of the patients newly diagnosed and TKI-resistant. However, expression levels of anti-apoptotic GCS and SK1 genes were significantly higher in TKI-resistant and blastic phase patients than that of other patients. Additionally, BCR/ABL expression levels were higher in newly diagnosed and TKI-resistant patients. Conclusion: Our results suggest that expression levels of bioactive sphingolipid genes might be novel markers for determination of drug resistance in CML patients. More importantly, they might be used as novel targets for more effective treatment of resistant CML patients.
Keywords: chronic myeloid leukemia; drug resistance; tyrosine kinase inhibitor; bioactive sphingolipids; ceramide