title: Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT.
abstract: A polymorphic variant of the phosphatase PTPN22 has been associated with increased risk for multiple autoimmune diseases. The risk allele is thought to function by diminishing antigen-receptor signals responsible for negative selection of autoreactive lymphocytes. We now show that PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL), a common malignancy of autoreactive B lymphocytes. We also show that overexpression of PTPN22 significantly inhibits antigen-induced apoptosis of primary CLL cells by blocking B-cell receptor (BCR) signaling pathways that negatively regulate lymphocyte survival. More importantly, we show that PTPN22 positively regulates the antiapoptotic AKT kinase, which provides a powerful survival signal to antigen-stimulated CLL cells. This selective uncoupling of AKT from other downstream BCR signaling pathways is a result of inhibition of a negative regulatory circuit involving LYN, CD22, and SHIP. Finally, we show that PTPN22 can be effectively down-regulated by the PKC inhibitors ruboxistaurin and sotrastaurin, resulting in enhanced killing of CLL cells exposed to proapoptotic BCR stimuli. Collectively, these data suggest that PTPN22 overexpression represents a protective mechanism that allows autoantigen-activated CLL cells to escape from negative selection and indicate that this mechanism could be exploited for therapeutic purposes by targeting PTPN22 with PKC inhibitors.
authors.affiliation: Molecular Hematology, International Centre for Genetic Engineering & Biotechnology, Campus A. Buzzati-Traverso, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Negro
authors.forename: Stefania
authors.initials: S
authors.lastname: Gobessi
authors.forename: Pablo G
authors.initials: PG
authors.lastname: Longo
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Dimitar G
authors.initials: DG
authors.lastname: Efremov
mesh_terms: D017951:Antigen Presentation / Q000502:physiology; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D015551:Autoimmunity / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000819:agonists / Q000378:metabolism*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D001324:Autoantigens; D051058:Oncogene Protein v-akt; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22