BCAT1 Enhances BCAA Production to Drive Myeloid Leukemia

Cellular metabolism reprogramming occurs in multiple types of cancer, but it is not well understood how metabolic changes regulate tumor progression. To better understand the role of α-amino acid metabolism in chronic myeloid leukemia (CML), Hattori and colleagues quantified blood plasma levels of 16 amino acids in mouse models of CML. During blast crisis (BC)-CML, plasma and intracellular levels of the branched-chain amino acids (BCAA) valine, leucine, and isoleucine were elevated compared with chronic phase (CP)-CML. BCAT1, a cytoplasmic aminotransferase that catalyzes BCAA transamination in both directions to promote BCAA breakdown or production, was upregulated in BC-CML compared with CP-CML. BCAT1 depletion reduced intracellular BCAA production and suppressed the colony-forming ability of BC-CML cells in vitro. In vivo, BCAT1 depletion extended survival in mice transplanted with BC-CML cells and promoted cellular differentiation. Further, serial transplantation of leukemic cells lacking BCAT1 failed to initiate disease. Consistent with these findings, peripheral blood samples from patients with BC-CML exhibited increased expression of BCAT1 compared with samples from healthy patients or patients with CP-CML, and analysis of data from 113 cases of CML in the Gene Expression Omnibus revealed that BCAT1 expression increased throughout disease progression from the CP to accelerated phase and finally to the BC phase. Further, BCAT1 was overexpressed in acute myeloid leukemia (AML), and high expression was associated with poorer survival. Inhibition of BCAT1 with gabapentin suppressed BC-CML cell-colony formation, but could be rescued by the addition of BCAAs, confirming that BCAT1 acts through BCAA production. In contrast, normal hematopoietic progenitor cells were minimally affected by gabapentin. Mechanistically, the oncogenic RNA binding protein MSI2 bound to the BCAT1 transcript to promote BCAT1 protein expression, and BCAAs acted downstream to promote mTORC1 activation and downstream S6K phosphorylation. The finding that BCAT1 enhances BCAA production to drive myeloid leukemia progression suggests the potential for therapeutic targeting of the BCAA metabolic pathway.

Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 2017;545:500–4.