Targeting death receptor-mediated apoptosis in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive disease with poor prognosis, is hindered by the inherent resistance of primary leukemia cells. Knowledge on therapeutic vulnerabilities in these malignant cells will provide opportunities for developing novel combinatory treatments for patients. Using label-free quantitative mass spectrometry and subcellular fractionation techniques, we systematically compared organelle-specific proteomes between Jurkat cells, an in vitro model for T-ALL, and a Jurkat mutant with increased resistance to death receptor-mediated apoptosis. By identifying several differentially regulated protein clusters, our data argued that extensive metabolic reprograming in the mitochondria, characterized by enhanced respiration and energy production, might allow cells to evade DR5-mediated cytotoxicity. Further analysis using clinical datasets demonstrated that the elevated expression of a three-gene signature, consisting of SDHA, IDH3A, and ANXA11, was significantly associated with poor survival of acute leukemia patients. Our analysis therefore provided a unique dataset for a mechanistic understanding of T-ALL and for the design of novel ALL treatments.

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