Reprogrammed cellular metabolism is a common characteristic observed in various cancers1,2. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2–BCAT1 axis drives cancer progression in myeloid leukaemia.
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We thank W. Pear, D. Baltimore and S. Lowe for plasmids, and S. Dalton, C. Jordan, B. Zimdahl, J. Ninomiya-Tsuji, K. Sai, K. Matsumoto, H. Hanafusa, T. Mizuno, Y. Kuwatsuka, Y. Minami and M. Merritt for discussions and comments on the manuscript. We also thank J. Nelson at the CTEGD Cytometry Shared Resource Laboratory, University of Georgia, for assistance in cell sorting, K. Sekimizu, C. West, M. Mandalasi and H. van der Wel for advice on radioisotope use, and K. MacKeil, J. Nist and K. Ogata for technical help. This work was supported by grants from the University of Georgia Research Foundation and the Heather Wright Cancer Research Fund (T.I.); by the Japan Society for the Promotion of Science Bilateral Open Partnership Joint Research Projects Program (M.T.); A.S.E. and the Complex Carbohydrate Research Center NMR facility were partly supported by the Southeast Center for Integrated Metabolomics, National Institutes of Health U24DK097209 and the Georgia Research Alliance.
Extended data figures
This file contains a Supplementary Discussion, Supplementary References and the uncropped blots.
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