Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation
Blood, The Journal of the American Society of Hematology, 2012•ashpublications.org
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 …
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 …
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 up-regulated JAK2 signaling. Neutralizing Ab 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.
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