Project description:High levels of branched-chain amino acid (BCAA) transaminase 1 (Bcat1) have been associated with adverse prognosis and drug resistance in several cancer types. However, the mechanistic role of Bcat1 in T-cell acute lymphoblastic leukemia (T-ALL) development is ill defined. Here, we used a mouse T-ALL model to show that Bcat1 is required for T-ALL development and maintenance. Using a NOTCH1 gain-of-function retroviral model of T-ALL, mouse cells genetically deficient for Bcat1 showed defects in developing leukemia. Amongst the pathways upregulated in Bcat1 KO delta E-NOTCH1 cells we found “DNA repair”, “apoptosis”, and “p53 pathway”. We thus hypothesize that Bcat1 may be implicated in cell cycle progression or apoptosis of T-ALL cells.
Project description:In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABLT315I-induced murine TKI-resistant CML model . Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro.
Project description: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.
