Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT

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作者：

R Negro，S Gobessi，PG Longo，Y He，ZY Zhang，L Laurenti，DG Efremov

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摘要：

A polymorphic variantfhe phosphatase PTPN22aseenssociated with increasediskorultipleutoimmune diseases.heiskllele ishoughtounctiony diminishingntigen-receptorignalsesponsibleor negativeelectionfutoreactive lymphocytes. We nowhowhat PTPN22 isarkedlyverexpressed inhronic lymphocytic leukemia (CLL),ommonalignancyfutoreactive lymphocytes. Welsohowhatverexpressionf PTPN22ignificantly inhibitsntigen-inducedpoptosisf primaryLLellsylocking-celleceptor (BCR)ignaling pathwayshat negativelyegulate lymphocyteurvival.ore importantly, wehowhat PTPN22 positivelyegulateshentiapoptoticKT kinase, which provides powerfulurvivalignalontigen-stimulatedLLells.hiselectivencouplingfKTromther downstreamCRignaling pathways isesultf inhibitionf negativeegulatoryircuit involving LYN,D22,ndHIP.inally, wehowhat PTPN22ane effectively down-regulatedyhe PKC inhibitorsuboxistaurinndotrastaurin,esulting in enhanced killingfLLells exposedo proapoptoticCRtimuli.ollectively,hese datauggesthat PTPN22verexpressionepresents protectiveechanismhatllowsutoantigen-activatedLLellso escaperom negativeelectionnd indicatehathisechanismoulde exploitedorherapeutic purposesyargeting PTPN22 with PKC inhibitors.

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关键词：

inhibitorsuboxistaurinndotrastaurin positivelyegulateshentiapoptoticKT primaryLLellsylocking-celleceptor PTPN22verexpressionepresents Welsohowhatverexpressionf

DOI：

10.1182/blood-2012-01-403162

被引量：

111

年份：

2012