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 originale | English |
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pagine (da-a) | 6278-6287 |
Numero di pagine | 10 |
Rivista | Blood |
Volume | 119 |
DOI | |
Stato di pubblicazione | Pubblicato - 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