Suppression of UCP2 alleviates leukemogenesis by enhancing branched amino acids induced oxidative stress via activating PI3K/AKT/mTOR signaling

Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis have been reported in various solid tumor models, its role in leukemogenesis remain elusive. Here, we demonstrated that UCP2 was highly expressed in AML, and it is significantly associated with chemoresistance and poor prognosis suggesting that UCP2 can be a potential biomarker for AML treatment. Mechanically, in vitro and in vivo silencing of UCP2 significantly impairs AML cell growth, survival and accompanied with the disruption of mitochondria homeostasis. Interestingly, RNA-seq analysis and metabolic mass spectrometry revealed that silencing UCP2 results in accumulation of branched chain amino acids (BCAA), which in turn induced oxidative stress through activating PI3K/AKT and mTOR signaling pathway. Additionally, lack of BCAA restored leukemic cell growth, cell survival and decreased mitochondria ROS production which is induced by inhibiting UCP2. Notably, supplementation of BCAA enhanced anti-tumor activity of Genipin, a selective inhibitor that targets UCP2, results in significant reduction of AML blasts, increased mice survival and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provide a novel strategy for leveraging the metabolic dependencies of leukemic cells.