Role of Branched Chain Amino Acid Transaminase 1 (BCAT1) in Acute Myeloid Leukemia [expression_BCAT1-KD #2]

The branched chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. By performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem cell (LSC) and non-LSC populations, we found the BCAA pathway enriched and BCAT1 overexpressed in LSCs. We show that BCAT1, which transfers -amino groups from BCAAs to -ketoglutarate (KG), is a critical regulator of intracellular KG homeostasis. Next to its role in the tricarboxylic acid (TCA) cycle KG is an essential co-factor for KG-dependent dioxygenases such as EGLN1 and the TET family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of KG leading to HIF1a protein degradation mediated by EGLN1. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. In contrast, overexpression (OE) of BCAT1 in leukaemia cells decreased intracellular KG levels and caused DNA hypermethylation via altered TET activity. BCAT1high AMLs displayed a DNA hypermethylation phenotype similar to cases carrying mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHwtTET2wt, but not IDHmut or TET2mut AMLs. Gene sets characteristic for IDHmut AMLs were enriched in IDHwtTETwtBCAT1high patient samples. BCAT1high AMLs showed robust enrichment for LSC signatures and paired sample analysis revealed a significant increase of BCAT1 levels upon disease relapse. In summary, by limiting intracellular KG, BCAT1 links BCAA catabolism to HIF1a stability and regulation of the epigenomic landscape. Our results suggest the BCAA-BCAT1-KG pathway as a therapeutic target to compromise LSC function in IDHwtTET2wt AML patients.

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Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, Bullinger L, Poschet G, Nonnenmacher Y, Barnert A, Bahr C, Zeisberger P, Przybylla A, Sohn M, Tönjes M, Erez A, Adler L, Jensen P, Scholl C, Fröhling S, Cocciardi S, Wuchter P, Thiede C, Flörcken A, Westermann J, Ehninger G, Lichter P, Hiller K, Hell R, Herrmann C, Ho AD, Krijgsveld J, Radlwimmer B, Trumpp A