Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) represents a therapeutically challenging, high-risk leukemia subtype whose comprehensive proteomic characterization remains limited. Our integrated 4D label-free proteomic analysis delineates a distinct molecular signature featuring profound oxidative phosphorylation (OxPhos) deficiency, characterized by compromised mitochondrial ATP synthesis and significant reductions in electron transport chain complexes I and IV. Single-cell RNA sequencing validation establishes that stem-like ETP-ALL populations exhibit substantially diminished ETC activity relative to T-lineage-differentiated counterparts. Pharmacological intervention using dichloroacetate to restore OxPhos functionality effectively suppresses leukemic proliferation and xenograft engraftment through ROS-mediated endoplasmic reticulum stress activation. Furthermore, we identify CD109 as an attractive immunophenotypic marker that not only distinguishes ETP-ALL from other hematologic malignancies but also defines a subset with enhanced ETC suppression and heightened metabolic vulnerability to dichloroacetate. These findings elucidate the mechanistic basis of mitochondrial dysregulation in ETP-ALL pathogenesis and nominate CD109 as a promising biomarker for targeted therapeutic strategies.