High BCAT1 Expression Mimics IDH Mutations in Acute Myeloid Leukemia

BCAA transaminase 1 (BCAT1) transfers α-amino groups from branched-chain amino acids (BCAA) to α-ketoglutarate (αKG) and is associated with aggressiveness in cancer; however, the mechanism by which BCAT1 drives tumorigenesis is unclear. Raffel, Falcone, Kneisel, and colleagues performed high-resolution proteomic analysis of human acute myeloid leukemia (AML) stem cell (LSC) and non–stem cell populations and found that the BCAA pathway was enriched and BCAT1 protein and transcripts were overexpressed in LSCs. Depletion of BCAT1, which catalyzes the first step of BAA degradation, suppressed the proliferation and survival of AML cells in vitro, and eliminated leukemic initiation in vivo, indicating a requirement for BCAT1 in AML LSCs. BCAT1 is a critical regulator for the homeostasis of αKG, which serves as a cofactor for EGL-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. BCAT1 depletion resulted in accumulation of αKG, leading to EGLN1-mediated degradation of HIF1α, and HIF1α overexpression was sufficient to restore cell growth and survival after BCAT1 knockdown. Conversely, BCAT1 overexpression decreased intracellular αKG levels and caused DNA hypermethylation through inhibition of TET2, mimicking the effects of IDH mutations in AML, as mutant IDH generates 2-hydroxyglutarate that inhibits EGLN1 and TET2. High BCAT1 expression was associated with poor survival in patients with ID1– and TET2–wild-type AML, but not in IDH- or TET2-mutant AML, consistent with the redundant role of BCAT1 overexpression and IDH mutations in suppressing TET2 activity. Moreover, high BCAT1 expression was associated with enrichment of leukemia stem-cell signature genes, and BCAT1 expression increased upon AML relapse. Collectively, these findings demonstrate that BCAT1 expression results in an αKG-dependent IDH mutant–like DNA hypermethylation phenotype. Thus, BCAT1 supports AML LSCs and associated therapy resistance and may serve as a therapeutic target in AML.

Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, et al. BCAT1 restricts αKG levels in AML stem cells leading to IDH^mut-like DNA hypermethylation. Nature 2017;551:384–8.

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