Genome-wide maps of H3K27me3 chromatin modification status regulated by branched chain amino acids (BCAA) metabolism in human acute leukemia

The branched-chain amino acid (BCAA) metabolism plays pleiotropic roles in homeostasis. Here we show that human acute leukemia-initiating cells (LICs), but not normal hematopoietic stem cells, are heavily addicted to the BCAA metabolism, irrespective of myeloid or lymphoid types. Human acute leukemia cells had a high level of BCAAs, transporting free BCAAs into the cytoplasm. Functional inhibition of BCAA transaminase-1 (BCAT1), a catalytic enzyme for BCAAs, induced apoptosis of human LICs, and suppressed reconstitution of human leukemia in xenograft models. Furthermore, deprivation of BCAAs from daily diet in mice transplanted with human LICs strongly inhibited their expansion and self-renewal in vivo. The BCAT1 inhibition inactivates the PRC2 function for epigenetic maintenance of stem cell signatures via downregulation of EZH2 and EED, critical PRC2 components, and inhibited the mTORC1 signaling for leukemia propagation. Thus, targeting the BCAA metabolism should be a powerful approach to erase cancer stemness in human acute leukemias.

支链氨基酸（branched-chain amino acid, BCAA）的代谢在机体稳态中发挥多效性作用。本研究证实，人类急性白血病起始细胞（acute leukemia-initiating cells, LICs）而非正常造血干细胞，对BCAA代谢呈现出强烈的依赖性，且该依赖性不受髓系或淋巴系分型影响。人类急性白血病细胞内BCAA水平较高，可将游离BCAA转运至细胞质中。作为BCAA催化酶的支链氨基酸转氨酶1（BCAA transaminase-1, BCAT1）经功能性抑制后，可诱导人类LICs发生凋亡，并在异种移植模型中抑制人类白血病的重建能力。进一步研究显示，在移植了人类LICs的小鼠中，通过日常饮食剥夺BCAA可显著抑制其体内扩增与自我更新能力。BCAT1抑制可通过下调多梳抑制复合体2（Polycomb Repressive Complex 2, PRC2）的关键组分EZH2与EED，灭活该复合物维持干细胞特征表观遗传状态的功能，并抑制介导白血病增殖的哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）信号通路。因此，靶向BCAA代谢有望成为根除人类急性白血病中肿瘤干细胞特性的有效策略。