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

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.

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

“…24 In the present study, we correlated pretreatment serum cytokines levels of these patients with pSTAT3 and Myc tumor cell expression. Of the 30 cytokines tested (Figure 6A), the only pretreatment cytokines that were significantly correlated with pSTAT3 expression were IL-10 (P ϭ .05), G-CSF (P ϭ .03), and TNF-␣ (P ϭ .04); none was correlated with Myc expression ( Figure 6A).…”

“…24 Because Myc is downstream of STAT3 in the signal pathway, we next examined Myc protein expression by IHC. Twenty-four of the same DLBCL tumors used for pSTAT3 expression were stained and 50% (12 of For personal use only.…”

“…24 Because Myc is downstream of STAT3 in the signal pathway, we next examined Myc protein expression by IHC. Twenty-four of the same DLBCL tumors used for pSTAT3 expression were stained and 50% (12 of For 24) were Myc positive (all nuclear) as defined by the criteria of Ն 30% of cells staining positive (Figure 2A-B). In cases (n ϭ 23) where both Myc and pSTAT3 IHC were performed, a positive pSTAT3 was more likely to have Myc expression, whereas a positive Myc stain did not inform pSTAT3 status ( Figure 2C).…”

“…Multiplex ELISA (30-plex) was performed as previously described 24 on available pretreatment patient serum (n ϭ 32) and correlated with Myc and pSTAT3 results from paired tumor biopsies.…”

Immune independent crosstalk between lymphoma and myeloid suppressor CD14+HLA-DRlow/negmonocytes mediates chemotherapy resistance

“…DLBCL cell lines Su-DHL2, Su-DHL6, OCI-Ly1, OCI-Ly7, OCILy3, OCI-Ly10, and MCL cell lines JEKO-1 and Granta-519 cells were gifts from Dr. Mamta Gupta and Dr. Thomas Witzig (Mayo Clinic, Rochester, MN) and maintained in culture as previously described ( 33 ,Table S2). …”