Elevated serum IL-10 levels in diffuse large B-cell lymphoma: A mechanism of aberrant JAK2 activation

Mamta Gupta, Jing Jing Han, Mary Stenson, Matthew Maurer, Linda Wellik, Guangzhen Hu, Steve Ziesmer, Ahmet Dogan, Thomas E. Witzig

Research output: Contribution to journalArticle

96 Scopus citations

Abstract

Cytokines are deregulated in cancers and can contribute to tumor growth. In patients with diffuse large-cell lymphoma (DLBCL), we observed higher levels of JAK/STAT pathway-related serum cytokines (ie, IL-6, IL-10, epidermal growth factor, and IL-2) compared with controls. Of these, only IL-10 activated the JAK2 pathway in lymphoma cells in vitro. Patients with high serum IL-10 had shorter event-free survival (EFS) than patients with low levels (P > .01) and high IL-10 was correlated with high lactase dehydrogenase (P ∇ .0085) and higher International Prognostic Index scores (P ∇ .01). To explore the mechanism by which IL-10 may contribute to an inferior EFS, we investigated the effect of IL-10 on the JAK2 pathway and found that the IL-10/IL-10 receptor complex upregulated JAK2 signaling. NeutralizingAb to IL-10 inhibited constitutive and IL-10-induced JAK2/STAT3 phosphorylation. JAK2 inhibition dephosphorylated JAK2 and STAT3 and caused an inhibitory effect on phospho-JAK2-positive DLBCL cells; there was a minimal effect on phospho-JAK2-negative cells. Apoptosis induced by JAK2 inhibition was dependent on inhibition of autocrine IL-10 and c-myc expression and independent of Bcl-2 family expression. These results provide the rationale for testing JAK2 inhibitors in DLBCL patients, and indicate that serum IL-10 may be a biomarker to identify patients more likely to respond to JAK2-targeted therapy.

Original languageEnglish (US)
Pages (from-to)2844-2853
Number of pages10
JournalBlood
Volume119
Issue number12
DOIs
StatePublished - Mar 22 2012

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Gupta, M., Han, J. J., Stenson, M., Maurer, M., Wellik, L., Hu, G., Ziesmer, S., Dogan, A., & Witzig, T. E. (2012). Elevated serum IL-10 levels in diffuse large B-cell lymphoma: A mechanism of aberrant JAK2 activation. Blood, 119(12), 2844-2853. https://doi.org/10.1182/blood-2011-10-388538