Search

We prove that the SH2-containing tyrosine phosphatase 1 (SHP-1) plays a prominent role as resistance determinant of imatinib (IMA) treatment response in chronic myelogenous leukemia cell lines (sensitive/KCL22-S and resistant/KCL22-R). Indeed, SHP-1 expression is significantly lower in resistant than in sensitive cell line, in which coimmunoprecipitation analysis shows the interaction between SHP-1 and a second tyrosine phosphatase SHP-2, a positive regulator of RAS/MAPK pathway. In KCL22-R SHP-1 ectopic expression restores both SHP-1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMA treatment. Consistently, SHP-2 knocking-down in KCL22-R reduces either STAT3 activation or cell viability after IMA exposure. Therefore, our data suggest that SHP-1 plays an important role in BCR-ABL–independent IMA resistance modulating the activation signals that SHP-2 receives from both BCR/ABL and membrane receptor tyrosine kinases. The role of SHP-1 as a determinant of IMA sensitivity has been further confirmed in 60 consecutive untreated patients with chronic myelogenous leukemia, whose SHP-1 mRNA levels were significantly lower in case of IMA treatment failure (P < .0001). In conclusion, we suggest that SHP-1 could be a new biologic indicator at baseline of IMA sensitivity in patients with chronic myelogenous leukemia.

Obesity is a consequence of imbalance of food intake and energy expenditure that results in storage of energy as fat, primarily in adipose tissue. MicroRNAs are non-coding RNAs that regulate gene expression in metabolic pathways and they are also involved in fat-cell development. The aim of this study was to evaluate whether microRNA dysfunction contributes to obesity. We analyzed, by microarray, the expression profile of 1,458 microRNAs in subcutaneous adipose tissue (SAT) from nondiabetic severely obese (n = 20) and nonobese adults (n = 8). Among 42 differently expressed microRNAs, we confirmed by reverse-transcription PCR (RT-PCR) that miR-519d was overexpressed whereas the protein levels of peroxisome proliferator-activated receptor-alpha (PPARA) (a predicted miR 519d target) were lower, at western analysis, in severely obese vs. nonobese subjects. We also show that miR-519d specifically and dose-dependently suppressed translation of the PPARA protein, and increased lipid accumulation during preadipocyte differentiation. Because PPARA plays a central role in fatty acid homeostasis, and in the transcriptional regulation of genes that are necessary for maintenance of the redox balance during the oxidative catabolism of fatty acids, we suggest that PPARA loss and miR-519d overexpression could be associated with metabolic imbalance and subsequent adipocyte hypertrophy in SAT during obesity.

CuZn-superoxide dismutase (SOD) plays a key role in mediating the cellular response to oxidative stress. Its expression in normal thymus was investigated by immunohistochemical techniques and CD3-, CD68- and cytokeratin-specific staining, in order to identify thymocytes, macrophages and epithelial components. Immunocytochemical studies showed an overall CuZn-SOD thymic distribution with a prevailing concentration within thymic medulla. The analysis of CuZn-SOD release by thymus-derived epithelial and fibroblast cell lines showed the ability of both cell lines to release the anti-oxidant enzyme, especially in the presence of stress conditions as represented by serum and nutrient deprivation. These data suggest that CuZn-SOD could be a relevant antioxidant paracrine molecule in human thymus.