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

Roberto Negro, Stefania Gobessi, Pablo G. Longo, Yantao He, Zhong-Yin Zhang, Luca Laurenti, Dimitar G. Efremov

Research output: Contribution to journalArticle

57 Citations (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.

Original languageEnglish
Pages (from-to)6278-6287
Number of pages10
JournalBlood
Volume119
Issue number26
DOIs
StatePublished - Jun 28 2012

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Lymphocytes
B-Cell Chronic Lymphocytic Leukemia
Autoimmunity
Phosphoric Monoester Hydrolases
Antigens
B-Lymphocytes
ruboxistaurin
Antigen Receptors
Autoantigens
Phosphotransferases
Cells
Apoptosis
Networks (circuits)
Autoimmune Diseases
Alleles
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. / Negro, Roberto; Gobessi, Stefania; Longo, Pablo G.; He, Yantao; Zhang, Zhong-Yin; Laurenti, Luca; Efremov, Dimitar G.

In: Blood, Vol. 119, No. 26, 28.06.2012, p. 6278-6287.

Research output: Contribution to journalArticle

Negro, Roberto ; Gobessi, Stefania ; Longo, Pablo G. ; He, Yantao ; Zhang, Zhong-Yin ; Laurenti, Luca ; Efremov, Dimitar G. / Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. In: Blood. 2012 ; Vol. 119, No. 26. pp. 6278-6287.
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