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- W2530199276 abstract "Abstract Signal regulatory protein-α (SIRPα) is a transmembrane receptor selectively expressed on myeloid and neuronal cells. The broadly expressed cell surface CD47 molecule acts as a major extracellular ligand. The SIRPα cytoplasmic tail contains ITIM motifs that upon CD47 binding mediate the recruitment and activation of the cytosolic tyrosine phosphatases SHP-1 and SHP-2. SIRPα signaling negatively regulates many signaling pathways leading to reduced tumor migration, survival and cell transformation. Interestingly, a reduced SIRPα expression has been found in >70% of acute myeloid leukemia (AML) patients, including APL (FAB M3). Since SIRPα-derived signals are involved in the inhibition of myeloid cell growth, reduced SIRPα expression might contribute the proliferative advantage of leukemic cells. We hypothesized that the reduced expression of SIRPα in APL might be the result of aberrant promoter hypermethylation, which could have potential relevance for innovative therapy. The aim of this study was therefore to investigate protein expression of SIRPα in pediatric APL and evaluate the methylation status of the PTPNS1 gene (encoding SIRPα). Immunocytochemical staining was performed on cryo-preserved cytospins using a commercially available antibody (Ab2971, Abcam). The leukemic cell lines THP-1, Kasumi-1 were used as positive controls. Negative controls were performed by omitting the first antibody and the inclusion of the ALL cell line CCRF-CEM. SIRPα protein expression was evaluated by two independent investigators by scoring the intensity of the staining: negative (−), low (+/−) and positive (+). Methylation specific PCR (MSP) was set up in order to study the methylation pattern of the PTPNS1 promoter in the APL cell line NB4 and 10 APL patient samples (containing >80% blasts). Two primer sets (named MSP1 and MSP2, respectively) were used which recognized different regions of the PTPNS1 promoter. SIRPα expression in THP-1 cells was high, while expression in Kasumi-1 cells was low. The lymphoblastic cell line CCRF-CEM did not express SIRPα. These findings were in agreement with results obtained by Western blotting using the same antibody. The APL cell line NB4 stained positive for SIRPα. In the APL patients, SIRPα expression was low (n=7) or absent (n=2) in 9/10 (90%) samples. Expression was high in 1 sample (10%). MSP revealed methylation in one part of the PTPNS1 promoter region. The MSP1 primer set showed both methylated and unmethylated bands in the NB4 cell line as well as in all 10 APL patient samples. No methylation was detected using the MSP2 primer set. In conclusion, we observed no to low expression of SIRPα in the majority of APL patient samples (90%). In addition, we observed methylation of the PTPNS1 promoter in APL patient samples, indicating that aberrant promoter methylation might be involved in the reduced SIRPα expression in pediatric APL. This could have important implications for future alternative treatment options for APL patients directed towards demethylation of the gene and re-expression of this inhibitory signaling protein." @default.
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- W2530199276 date "2007-11-16" @default.
- W2530199276 modified "2023-10-16" @default.
- W2530199276 title "Methylation of the PTPNS1 Promoter Region in Pediatric Acute Promyelocytic Leukemia." @default.
- W2530199276 doi "https://doi.org/10.1182/blood.v110.11.4315.4315" @default.
- W2530199276 hasPublicationYear "2007" @default.
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