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. Overall design: We examined the alteration of H3K27me3 histone modification status in human acute leukemia cells in vitro and in vivo. Briefly, (acute myeloid leukemia (AML) cell line THP-1, primary CD34+ acut lymphoblastic leukemia (ALL) cells and primary CD34+ AML cells were treated with or without gabapentin (GABA) in vitro, and subsequently submitted to ChIP-Seq analysis. We also evaluated the alteration of H3K27me3 histone modification status of primary ALL cells in vivo. Briefly, primary CD34+ ALL cells were transplanted into the immunodeficient mice (NSG mice), and the recipients mice were fed with control diets or BCAA=free diets. After the dietary restriction of BCAAs, reconstituted human CD34+ ALL cells were harvested from the recipient mice, and then submitted to ChIP-Seq analysis.