Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant Janus kinase 2 activation.
Source
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States;
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 (IL-6, IL-10, EGF, IL-2) vs 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>0.01) and high IL-10 correlated with high LDH (p=0.0085) and higher International Prognostic Index scores (p=0.01). 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-10R complex upregulated JAK2 signaling. Neutralizing antibody to IL-10 inhibited constitutive as well as 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 minimal effect on phospho-JAK2 negative cells. Apoptosis induced by JAK2 inhibition was dependent upon 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.
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