An active TCA cycle state defines a high-risk acute lymphoblastic leukemia subtype

Acute lymphoblastic leukemia (ALL) exhibits profound clinical heterogeneity; however, its metabolic determinants remain poorly defined. By constructing a single-cell transcriptional metabolic landscape, we identified the tricarboxylic acid (TCA) cycle as the dominant source of metabolic heterogeneity in leukemic cells, enabling their stratification into three distinct states. The highly active (H-A) TCA cycle state correlates with developmental immaturity. Patients enriched in this state, classified as the H-A subtype, have inferior survival and exhibit resistance to venetoclax. Regulatory network analysis identified PA2G4 and YBX1 as the master regulators of this high-risk subtype. Their inhibition attenuated TCA cycle flux and synergized with venetoclax to suppress leukemia cell survival. Collectively, this study defines a novel, metabolically driven, high-risk ALL subtype and reveals a druggable transcriptional-metabolic axis to overcome therapy resistance.