The BCAA metabolism maintains transcription of EZH2 and EED in human primary acute leukemia in vivo. (A) Quantitative real-time PCR analysis of EZH2 and EED transcription in primary AML and ALL cells in NSG mice fed the control and BCAA-free diet. Results of 3 independent xenotransplantation experiments using cells from 3 patients (PDX AML1, PDX AML3, and PDX ALL5) are shown. (B) Representative results of EED and EZH2 protein levels in hCD45⁺ cells purified from the NSG mice fed the control diet (n = 2) or BCAA-free diet (n = 2). (C) The schematic summary of the role of BCAA metabolism in human leukemias. Leukemia cells express LAT transporters to uptake BCAA. The BCAA catabolism generates critical substrates for the OXPHOS pathway to provide energy and for the non-EAA pathway to synthesize proteins. α-KG is a resultant product of both pathways. Although α-KG is used at the stage of BCAA to BCKA catabolism, both pathways produce α-KG to prevent decrease in the cellular α-KG level or even to increase its level in leukemia cells. The BCAA metabolism is required for the PRC2 function to maintain stemness in leukemia cells, at least through stimulating EZH2 and EED transcription. ∗P < .05, ∗∗P < .01, panel A, mean ± SEM.