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

Luca Laurenti, R Negro, S Gobessi, Pg Longo, Y He, Z Zhang, Dg Efremov

Risultato della ricerca: Contributo in rivistaArticolo in rivista

65 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)6278-6287
Numero di pagine10
RivistaBlood
Volume119
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Antigen Presentation
  • Autoantigens
  • Autoimmunity
  • Cell Survival
  • Cells, Cultured
  • Enzyme Activation
  • Gene Knockdown Techniques
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lymphocyte Activation
  • Oncogene Protein v-akt
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Substrate Specificity
  • Transfection
  • Up-Regulation

Fingerprint Entra nei temi di ricerca di 'Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT'. Insieme formano una fingerprint unica.

Cita questo