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http://purl.uniprot.org/citations/15539083http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/15539083http://www.w3.org/2000/01/rdf-schema#comment"

Objective

Acquired resistance to imatinib mesylate (STI571) in chronic myelogenous leukemia (CML) patients has become a serious clinical problem. We previously established STI571-resistant sublines (designated KTR cells) from the CML cell line KT-1. T cell protein tyrosine phosphatase (TC-PTP) was markedly downregulated in all KTR cells compared to parental KT-1 cells. Therefore, we examined whether the suppression of TC-PTP expression might contribute to imatinib mesylate-resistance in KTR cells.

Materials and methods

We transduced the nuclear isoform of TC-PTP (TC45) and catalytically inactive TC45-D182A cDNAs into KTR cells by retroviral gene transfer. Subsequently, we analyzed the sensitivity to imatinib mesylate and the status of signaling pathways in the transduced cells.

Results

The overall levels of STAT5 phosphorylation were significantly higher in KTR cells as compared to KT-1 cells, but reconstitution of TC-PTP in KTR cells resulted in a dramatic decrease of STAT5 phosphorylation. Furthermore, STAT5 phosphorylation was ablated by imatinib mesylate in KT-1 cells but remained elevated in KTR cells. In contrast, we observed no difference in BCR-ABL or JAK2 phosphorylation and no difference in activation of other signaling pathways. Importantly, reconstitution of TC-PTP in KTR cells to levels found in parental KT-1 cells restored their sensitivity to imatinib mesylate as monitored by reduced proliferation and increased apoptosis.

Conclusions

We have demonstrated that forced expression of TC-PTP in imatinib mesylate-resistant KTR cells can restore sensitivity to imatinib mesylate. Our studies indicate that loss of TC-PTP may represent a novel mechanism by which CML cells can acquire imatinib mesylate-resistance."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.org/dc/terms/identifier"doi:10.1016/j.exphem.2004.07.024"xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Miyakawa Y."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Shimizu T."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Ikeda Y."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Iwata S."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Morimoto C."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Tiganis T."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Kizaki M."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/author"Kuribara A."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/date"2004"xsd:gYear
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/name"Exp Hematol"xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/pages"1057-1063"xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/title"A novel mechanism for imatinib mesylate (STI571) resistance in CML cell line KT-1: role of TC-PTP in modulating signals downstream from the BCR-ABL fusion protein."xsd:string
http://purl.uniprot.org/citations/15539083http://purl.uniprot.org/core/volume"32"xsd:string
http://purl.uniprot.org/citations/15539083http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/15539083
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http://purl.uniprot.org/uniprot/#_P17706-mappedCitation-15539083http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/15539083
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http://purl.uniprot.org/uniprot/P17706http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/15539083
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