Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation.
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.
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA. gupta.mamta@mayo.edu
Mamta
M
Gupta
Jing Jing
JJ
Han
Mary
M
Stenson
Matthew
M
Maurer
Linda
L
Wellik
Guangzhen
G
Hu
Steve
S
Ziesmer
Ahmet
A
Dogan
Thomas E
TE
Witzig
D014408:Biomarkers, Tumor / Q000097:blood*; D015153:Blotting, Western; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016753:Interleukin-10 / Q000097:blood*; D053614:Janus Kinase 2 / Q000276:immunology / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood* / Q000276:immunology / Q000401:mortality; D034741:RNA, Small Interfering; D053701:Receptors, Interleukin-10 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D014408:Biomarkers, Tumor; C508609:IL10 protein, human; D034741:RNA, Small Interfering; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; C507924:JAK2 protein, human; D053614:Janus Kinase 2