Browsing by Author "Li, Juan"

Now showing 1 - 2 of 2
  • Thumbnail Image
    ItemOpen Access
    High IL2RA mRNA expression is an independent adverse prognostic biomarker in core binding factor and intermediate-risk acute myeloid leukemia
    (2019-06-06) Du, Wen; He, Jing; Zhou, Wei; Shu, Simin; Li, Juan; Liu, Wei; Deng, Yun; Lu, Cong; Lin, Shengyan; Ma, Yaokun; He, Yanli; Zheng, Jine; Zhu, Jiang; Bai, Lijuan; Li, Xiaoqing; Yao, Junxia; Hu, Dan; Gu, Shengqing; Li, Huiyu; Guo, Anyuan; Huang, Shiang; Feng, Xiaolan; Hu, Dong
    Abstract Background Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML. Methods In a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann–Whitney U test, Fisher exact test, logistic regression, Kaplan–Meier and Cox regression analyses were used. Results In AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001). Conclusions High IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.
  • Thumbnail Image
    ItemOpen Access
    Parkin coregulates glutathione metabolism in adult mammalian brain
    (2023-01-23) El Kodsi, Daniel N.; Tokarew, Jacqueline M.; Sengupta, Rajib; Lengacher, Nathalie A.; Chatterji, Ajanta; Nguyen, Angela P.; Boston, Heather; Jiang, Qiubo; Palmberg, Carina; Pileggi, Chantal; Holterman, Chet E.; Shutinoski, Bojan; Li, Juan; Fehr, Travis K.; LaVoie, Matthew J.; Ratan, Rajiv R.; Shaw, Gary S.; Takanashi, Masashi; Hattori, Nobutaka; Kennedy, Christopher R.; Harper, Mary-Ellen; Holmgren, Arne; Tomlinson, Julianna J.; Schlossmacher, Michael G.
    Abstract We recently discovered that the expression of PRKN, a young-onset Parkinson disease-linked gene, confers redox homeostasis. To further examine the protective effects of parkin in an oxidative stress model, we first combined the loss of prkn with Sod2 haploinsufficiency in mice. Although adult prkn−/−//Sod2± animals did not develop dopamine cell loss in the S. nigra, they had more reactive oxidative species and a higher concentration of carbonylated proteins in the brain; bi-genic mice also showed a trend for more nitrotyrosinated proteins. Because these redox changes were seen in the cytosol rather than mitochondria, we next explored the thiol network in the context of PRKN expression. We detected a parkin deficiency-associated increase in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) in murine brain, PRKN-linked human cortex and several cell models. This shift resulted from enhanced recycling of GSSG back to GSH via upregulated glutathione reductase activity; it also correlated with altered activities of redox-sensitive enzymes in mitochondria isolated from mouse brain (e.g., aconitase-2; creatine kinase). Intriguingly, human parkin itself showed glutathione-recycling activity in vitro and in cells: For each GSSG dipeptide encountered, parkin regenerated one GSH molecule and was S-glutathionylated by the other (GSSG + P-SH $$\to$$ → GSH + P-S-SG), including at cysteines 59, 95 and 377. Moreover, parkin’s S-glutathionylation was reversible by glutaredoxin activity. In summary, we found that PRKN gene expression contributes to the network of available thiols in the cell, including by parkin’s participation in glutathione recycling, which involves a reversible, posttranslational modification at select cysteines. Further, parkin’s impact on redox homeostasis in the cytosol can affect enzyme activities elsewhere, such as in mitochondria. We posit that antioxidant functions of parkin may explain many of its previously described, protective effects in vertebrates and invertebrates that are unrelated to E3 ligase activity.