Abstract 429: A novel regulatory role of FLT3/ITD mutation in lipid metabolism of leukemia cells: The mechanism and therapeutic implications

Abstract Internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3/ITD), is a common type of activating mutation and frequently detected in AML. FLT3/ITD is associated with poor prognosis of AML. In this study, we investigated the regulation of FLT3/ITD mutation on sterol regulatory element-binding protein (SREBP) and the therapeutic vulnerabilities of lipid metabolism in FLT3/ITD leukemia. With the transcriptomics analysis we found that FLT3/ITD controlled lipid metabolism via the transcription factor SREBP. The analysis of TCGALAML dataset revealed that a gene signature involved in fatty acid and cholesterol metabolism, which is regulated by SREBP, was upregulated in FLT3/ITD patients compared with FLT3/wild-type patients. The upregulation of SREBP protein expression in FLT3/ITD leukemia was confirmed using a genetically engineered mouse model. We further demonstrated that FLT3/ITD regulates the protein degradation of SREBP through the PI3K/AKT-GSK3β axis. The metabolomics analysis further showed that FLT3/ITD primarily regulates glycerophospholipid synthesis, which contribute to the key structure lipid in the membrane, specifically, the cardiolipin. Moreover, pharmacologic inhibition of SREBP activation and its downstream enzyme fatty acid synthase (FASN) sensitized FLT3-ITD AMLs to the treatment of FLT3 inhibitor quizartinib. Collectively, our findings reveal a novel regulation of FLT3-ITD in metabolic reprogramming and indicate a targetable vulnerability in a subset of refractory leukemia. Citation Format: Yumin Hu, Feng Yin, Mingyue Zhao, Wenhua Lu, Tiantian Yu. A novel regulatory role of FLT3/ITD mutation in lipid metabolism of leukemia cells: The mechanism and therapeutic implications abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 429.