👤 Mar Bellido

T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3. Show less

The Apolipoprotein A-V (apoA-V) gene promoter polymorphism -1131T>C modulates triacylglycerol (TG) concentrations. We evaluate whether this polymorphism could be involved in the interindividual variability observed during postprandial lipemia. Fifty-one healthy apo E3E3 male volunteers [12 with -1131CC/CT genotype, and 39 with -1131TT genotype] underwent a Vitamin A fat-load test consisting of 1g of fat/kg body weight and 60,000IU of Vitamin A. Blood samples were taken at time 0 and every hour until the 6th and every 2h and 30 min until the 11th. Cholesterol (Chol) and TG were determined in plasma and Chol, TG, ApoB-100, ApoB-48, and retinyl palmitate (RP) were determined in lipoprotein fractions. Data of postprandial lipemia revealed that subjects with the -1131CT/CC genotype had a higher postprandial response of total plasma TG (p=0.043), large triacylglycerol-rich lipoproteins-TG (TRL-TG) (p=0.002), large TRL-Chol (p=0.004), small TRL-Chol (p=0.004) and small TRL-RP (p=0.001) than subjects with the -1131TT genotype. The modifications observed in postprandial lipoprotein metabolism in subjects with the apoA-V -1131T>C polymorphism could be involved in the increased fasting plasma TG concentrations previously described in carriers of the C allele. Show less