Cancer progression by reprogrammed BCAA metabolism in myeloid leukemia

Summary

Reprogrammed cellular metabolism is a common characteristic observed in various cancers ^{1, 2} . However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for the branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukemia (CML). BCAT1 is up-regulated during CML progression and promotes BCAA production in leukemia cells by aminating the branched-chain keto acids. Blocking BCAT1 expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML (BC-CML) both in vitro and in vivo. Stable isotope tracer experiments combined with NMR-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 via BCAA production in BC-CML cells. Importantly, BCAT1 expression not only is activated in human BC-CML and de novo acute myeloid leukemia 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 BC-CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukemia.