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

Mamta Gupta, Jing Jing Han, Mary Stenson, Matthew Maurer, Linda Wellik, Guangzhen Hu, Steve Ziesmer, Ahmet Dogan, Thomas Elmer Witzig

Research output: Contribution to journalArticle

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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 upregulated JAK2 signaling. NeutralizingAb 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.

Original languageEnglish (US)
Pages (from-to)2844-2853
Number of pages10
JournalBlood
Volume119
Issue number12
DOIs
StatePublished - Mar 22 2012

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Lymphoma, Large B-Cell, Diffuse
Interleukin-10
Chemical activation
Cells
Serum
Disease-Free Survival
Interleukin-10 Receptors
Cytokines
Lactase
Phosphorylation
Biomarkers
Epidermal Growth Factor
Interleukin-2
Tumors
Interleukin-6
Lymphoma
Neoplasms
Oxidoreductases
Apoptosis

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Elevated serum IL-10 levels in diffuse large B-cell lymphoma : A mechanism of aberrant JAK2 activation. / Gupta, Mamta; Han, Jing Jing; Stenson, Mary; Maurer, Matthew; Wellik, Linda; Hu, Guangzhen; Ziesmer, Steve; Dogan, Ahmet; Witzig, Thomas Elmer.

In: Blood, Vol. 119, No. 12, 22.03.2012, p. 2844-2853.

Research output: Contribution to journalArticle

Gupta, M, Han, JJ, Stenson, M, Maurer, M, Wellik, L, Hu, G, Ziesmer, S, Dogan, A & Witzig, TE 2012, 'Elevated serum IL-10 levels in diffuse large B-cell lymphoma: A mechanism of aberrant JAK2 activation', Blood, vol. 119, no. 12, pp. 2844-2853. https://doi.org/10.1182/blood-2011-10-388538
Gupta, Mamta ; Han, Jing Jing ; Stenson, Mary ; Maurer, Matthew ; Wellik, Linda ; Hu, Guangzhen ; Ziesmer, Steve ; Dogan, Ahmet ; Witzig, Thomas Elmer. / Elevated serum IL-10 levels in diffuse large B-cell lymphoma : A mechanism of aberrant JAK2 activation. In: Blood. 2012 ; Vol. 119, No. 12. pp. 2844-2853.
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AU - Maurer, Matthew

AU - Wellik, Linda

AU - Hu, Guangzhen

AU - Ziesmer, Steve

AU - Dogan, Ahmet

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AB - 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 upregulated JAK2 signaling. NeutralizingAb 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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