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Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia.

ABSTRACT: 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.

SUBMITTER: Song X

PROVIDER: S-EPMC9033339 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia.

Song Xiaolei X Wu Xiaojing X Zhang Zihan Z Cui Zhangxiu Z Zheng Yong Y Sun Jian J

BioMed research international 20220415

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 be ...[more]

PMID: 35463978

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Project description:BackgroundB-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. Even though significant progresses have been made in the treatment of B-ALL, some pediatric B-ALL have still poor prognosis. The identification of tumor autoantibodies may have utility in early cancer diagnosis and immunotherapy. In this study, we used serological proteome analysis (SERPA) to screen serum autoantibodies of pediatric B-ALL, aiming to contribute to the early detection of B-ALL in children.MethodsThe total proteins from three pooled B-ALL cell lines (NALM-6, REH and BALL-1 cells) were separated using two-dimensional gel electrophoresis (2-DE), which was followed by Western blot by mixed serum samples from children with B-ALL (n=20) or healthy controls (n=20). We analyzed the images of 2-D gel and Western blot by PDQuest software, and then identified the spots of immune responses in B-ALL samples compared with those in control samples. The proteins from spots were identified using mass spectrometry (MS). The autoantibodies against alpha-enolase (α-enolase) and voltage-dependent anion-selective channel protein 1 (VDAC1) were further validated in sera from another 30 children with B-ALL and 25 normal individuals by the use of enzyme-linked immunosorbent assay (ELISA). The protein expression levels of the candidate antigens α-enolase and VDAC1 in B-ALL were thoroughly studied by immunohistochemical analysis.ResultsUtilizing the SERPA approach, α-enolase and VDAC1 were identified as candidate autoantigens in children with B-ALL. The frequencies of autoantibodies against α-enolase and VDAC1 in children with B-ALL were 27% and 23% by using ELISA analysis, respectively, which were significantly higher than those in normal controls (4% and 0, p<0.05). Immunohistochemical analysis showed the expression of α-enolase and VDAC1 was positive in 95% and 85% of B-ALL patients, respectively, but negative expression levels were showed in the control group.ConclusionsThis study incidated that α-enolase and VDAC1 may be the autoantigens associated with B-ALL. Therefore, α-enolase and VDAC1 autoantibodies may be the potential serological markers for children with B-ALL.

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Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia.

Publications

Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia.

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