BCAA catabolism mediates POU2AF1 propionylation to enhance T-ALL development.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive, life-threatening hematological malignancy with limited therapeutic regimens. While metabolic reprogramming is known to play critical roles in leukemogenesis, how distinct metabolic pathways orchestrate T-ALL pathogenesis remains largely unknown. We herein aim to unravel how the branched-chain amino acid (BCAA) metabolism fine-tunes T-ALL cell fates. METHODS: Metabolomic and transcriptomic analyses were performed to identify branched-chain amino acid transaminase 1 (BCAT1)-associated metabolic and molecular alterations. Functional studies in murine T-ALL models were conducted to evaluate the role of BCAT1 in leukemia development, including the assessment of leukemia burden by flow cytometry during T-ALL development. Biochemical and molecular assays were used to assess POU2AF1 propionylation and its downstream signaling. Clinical datasets were analyzed to investigate the clinical relevance of BCAT1 in T-ALL. RESULTS: We revealed that BCAT1 could serve as a critical driver to sustain T-ALL initiation and progression. BCAT1 was highly expressed in both murine and human T-ALL cells and was critical for the self-renewal and homing capacities of leukemia cells. Mechanistically, BCAT1-mediated BCAA catabolism promoted the propionylation of transcriptional coactivator POU2AF1, which further enhanced its ability to transactivate SLC7A11 expression to suppress ferroptosis and support the proliferation of T-ALL cells. Moreover, BCAT1 expression levels were strongly correlated with poor prognosis in T-ALL patients. Combined treatment with dietary BCAA restriction and immune checkpoint blockade synergistically inhibited T-ALL progression. CONCLUSION: Our findings reveal a novel mechanism whereby BCAA catabolism mediates ferroptosis resistance through POU2AF1 propionylation during T-ALL progression. Therapeutic blockade of the BCAT1-POU2AF1-SLC7A11 axis holds considerable translational potential in T-ALL treatment.