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Heterogeneous expression and function of IL-21R and susceptibility to IL-21−mediated apoptosis in follicular lymphoma cells
- Source :
- Experimental Hematology. 38:373-383
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
Abstract
- Objective Interleukin (IL)-21, a member of the IL-2 family, has antitumor activity and is now being tested in non-Hodgkin's lymphoma in combination with anti-CD20 antibodies. IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies. We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells. Materials and Methods IL-21R expression was studied by reverse transcription polymerase chain reaction, immunofluorescence, and Western blot analyses. Apoptosis was measured by Annexin-V−propidium iodide staining. Signaling via IL-21R was studied using antibodies specific for phosphorylated Janus-activating kinase and signal transducers and activators of transcription proteins by Western Blot. Results IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples. However, cells from areas of diffuse growth in FL and from two diffuse lymphomas evolved from previous FL, showed low IL-21R expression. The latter were also resistant to IL-21−mediated apoptosis. Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation. This cell line was IL-21R−positive, whereas five of six nonresponsive cell lines showed very low IL-21R expression. Intriguingly, one of the IL-21-resistant cell lines (DOHH2) expressed high levels of IL-21R. Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21−responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression. Conclusion These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21−mediated effects in some FL cells.
- Subjects :
- Cancer Research
Follicular lymphoma
Apoptosis
Suppressor of Cytokine Signaling Proteins
Biology
Translocation, Genetic
Cell Line, Tumor
Gene expression
Genetics
medicine
Humans
SOCS3
Lymphoma, Follicular
Molecular Biology
Janus Kinases
Chromosomes, Human, Pair 14
Kinase
Interleukins
Interleukin-21 Receptor alpha Subunit
Janus Kinase 3
Cell Biology
Hematology
medicine.disease
Molecular biology
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Reverse transcription polymerase chain reaction
STAT Transcription Factors
Suppressor of Cytokine Signaling 3 Protein
Cell culture
Signal transduction
Chromosomes, Human, Pair 18
Signal Transduction
Subjects
Details
- ISSN :
- 0301472X
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Experimental Hematology
- Accession number :
- edsair.doi.dedup.....4cd32a205f8216526fcc80b53805705f