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- W989813303 abstract "Mutations in FLT3 receptor tyrosine kinase are common in Acute Myeloid Leukemia (AML) and confer a worse prognosis. Ceramide, a bioactive sphingolipid, is synthesized de novo by Ceramide Synthases (CerS) and mediates cancer cell death in response to various chemotherapeutic agents. This study investigates the biological role of ceramide lipid in FLT3-positive AML pathogenesis. We show that AML cell lines and patient samples expressing FLT3 have suppressed CerS1 expression and lower levels of its product C18-ceramide compared with FLT3 negative AML cells. Silenced FLT3 expression or its pharmacological inhibition increased CerS1 and C18-ceramide levels while FLT3 overexpression suppressed them. The increase in C18-ceramide after FLT3 inhibition is required for cell death as silencing CerS1 expression or inhibiting its enzymatic activity protected from FLT3 inhibitors-induced cell death. Targeting FLT3 resulted in C18-ceramide dependent mitophagy, as determined by increased LC3B-II levels and formation of autophagosomes around mitochondria. Mechanistically, C18-ceramide accumulated in the mitochondria to bind directly to LC3B-II recruiting autophagosomal membranes for the execution of mitophagy. This process was accompanied by mitochondrial depolarization, decreased ATP generation, and DRP-1 oligomerization. In summary, our novel study is the first to highlight the importance of ceramide metabolism in AML oncogenesis by showing that FLT3 suppresses CerS1 expression and ceramide generation while its inhibition reactivates CerS1/C18-ceramide axis leading to lethal mitophagy and AML cell death." @default.
- W989813303 created "2016-06-24" @default.
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- W989813303 date "2015-04-01" @default.
- W989813303 modified "2023-10-16" @default.
- W989813303 title "Ceramide Mediated Lethal Mitophagy: A Novel Cell Death Mechanism in FLT3 Targeted Therapy for Acute Myeloid Leukemia" @default.
- W989813303 doi "https://doi.org/10.1096/fasebj.29.1_supplement.147.1" @default.
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