Bcat1-flox Mouse

Bcat1, short for branched-chain amino acid transaminase 1, is an enzyme that initiates the catabolism of branched-chain amino acids (BCAAs) like leucine. It plays a crucial role in BCAA metabolism, which is associated with various biological processes such as providing macromolecule precursors, and is linked to important metabolic and signaling pathways [4].

In cancer, increased Bcat1 expression has been associated with aggressive phenotypes. For example, in gastric cancer, a gain-of-function mutation (Bcat1E61A) with around 2.8% enrichment in clinical samples boosts BCAA catabolism, accelerates cell growth and motility, and promotes tumor development by directly interacting with RhoC [1]. In acute myeloid leukaemia (AML), Bcat1 restricts α-ketoglutarate (αKG) levels in AML stem cells, leading to IDHmut-like DNA hypermethylation. Knockdown of Bcat1 in leukaemia cells causes αKG accumulation, resulting in growth and survival defects and abrogating leukaemia-initiating potential [2]. In glioblastoma, Bcat1 is upregulated selectively in IDH wildtype tumors. Targeting Bcat1 combined with α-ketoglutarate triggers metabolic synthetic lethality in IDHWT glioblastoma cells, as loss of Bcat1 leads to metabolic alterations that are augmented by α-ketoglutarate treatment [3].

In conclusion, Bcat1 is essential in BCAA metabolism, and its dysregulation is implicated in multiple disease conditions, especially cancers. Gene knockout and related functional studies in mouse models have been instrumental in revealing its role in promoting cell growth, motility, and tumor development in cancer, and in regulating stem-cell-related functions in AML. These findings provide potential therapeutic targets for treating such diseases.