BCAA catabolism mediates POU2AF1 propionylation to enhance T-ALL development

Abstract

Abstract
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. Here, we revealed that the first rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain amino acid transaminase 1 (BCAT1), could serve as a critical driver to sustain T-ALL initiation and progression. BCAT1 ishighly expressed in both murine and human T-ALL cells and is 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 stronglycorrelated with poor prognosis inT-ALL patients. Combinedtreatment with dietaryBCAA restriction and immune checkpoint blockade synergistically inhibited T-ALL progression. Our findings reveala novel mechanism whereby BCAA catabolism mediates ferroptosis resistance through POU2AF1 propionylation during T-ALL progression. Therapeutic blockade of the BCAT1-POU2AF1-SLC7A11 axis holds great translational potential in T-ALL treatment.