Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant Janus kinase 2 activation
Menée sur des cultures cellulaires de lymphome diffus à grandes cellules B, cette étude identifie un mécanisme par lequel la cytokine IL-10 induit une activation anormale de JAK2
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.
Blood 2012