Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin's lymphoma

Fischer, M; Bijman, Marcel N.A.; Molin, Daniël; Cormont, F.; Uyttenhove, Catherine; Snick, Jacques Van; Sundström, Christer; Enblad, Gunilla; Nilsson, Gunnar

doi:10.1038/sj.leu.2403123

Cited by 58 publications

(46 citation statements)

References 27 publications

(27 reference statements)

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“…Beside the role of IL-9 during immune responses, its growth factor and anti-apoptotic activities on transformed cells suggest a potential role in tumorigenesis. Indeed, IL-9 overexpression induced thymic lymphomas in mice (Renauld et al, 1994), and IL-9 production is associated with Hodgkin's lymphoma (Merz et al, 1991;Fischer et al, 2003) and HTLV-I transformed T cells (Kelleher et al, 1991) in humans. Moreover, in vitro, dysregulation of the IL-9 response is associated with autonomous cell growth and malignant transformation of lymphoid cells showing constitutive activation of the JAK-STAT pathway.…”

Section: Introductionmentioning

confidence: 99%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokineindependent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.

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Section: Introductionmentioning

confidence: 99%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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“…cDNA array analysis revealed that interleukin (IL)-9 was strongly expressed in SNK-6 and SNT-8 cells. Furthermore, IL-9 has been reported to be expressed in some malignant lymphomas, such as Hodgkin's disease and large-cell anaplastic lymphoma (22,23), and to act as an autocrine growth factor for Hodgkin and Reed-Sternberg cells (24).…”

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confidence: 99%

Expression of Interleukin-9 in Nasal Natural Killer/T-Cell Lymphoma Cell Lines and Patients

Nagato

Kobayashi

Kishibe

et al. 2005

Clinical Cancer Research

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Purpose: Nasal natural killer (NK)/T-cell lymphoma is associated with EBV and has distinct clinical and histologic features. However, little is known about its genetic features. In this study, we examined the genes expressed by SNK-6 and SNT-8 cells, which were established from nasal NK/T-cell lymphomas, and found that interleukin (IL)-9 was specifically expressed in these two cell lines. Experimental Design: cDNA array was used to examine the genes expressed by SNK-6 and SNT-8 cells. Expression of IL-9 and IL-9 receptor was investigated by reverse transcription-PCR, ELISA, and flow cytometry. Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Immunohistologic staining and ELISA were used to examine IL-9 expression in biopsies and sera from patients, respectively. Results: In cDNA array, expression of IL-9 mRNA was much higher in SNK-6 and SNT-8 cells than in NK-92 cells from non-nasal NK-cell lymphoma and peripheral blood mononuclear cells from healthy volunteers. Furthermore, IL-9 was specifically expressed by SNK-6 and SNT-8 cells but not by other NK-cell, NK-likeT-cell, and T-cell lymphoma/leukemia cell lines. IL-9 receptor was also expressed on the surfaces of SNK-6 and SNT-8 cells. An IL-9-neutralizing antibody inhibited the growth of these two cell lines, whereas recombinant human IL-9 enhanced their growth. Most significantly, IL-9 was present in biopsies and sera from patients with this lymphoma. Conclusions:These results suggest that IL-9 plays an important role innasal NK/T-cell lymphoma possibly via an autocrine mechanism.

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“…[7][8][9][10][11][12] Methods previously employed in the identification of biomarkers have included enzyme-linked immunosorbent assays, immunohistochemistry of tissue microarrays, immunoradiometric assays, reverse transcriptase-polymerase chain reaction, gene and protein expression profiling and mass spectrometry-based methods. [13][14][15] To date, the identification of biomarkers in HL has been limited to known proteins for which there exist antibodies.…”

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confidence: 99%

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

Wallentine

Kim

Seiler

et al. 2007

Laboratory Investigation

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Mass spectrometry-based proteomics in conjunction with liquid chromatography and bioinformatics analysis provides a highly sensitive and high-throughput approach for the identification of proteins. Hodgkin lymphoma is a form of malignant lymphoma characterized by the proliferation of Reed-Sternberg cells and background reactive lymphocytes. Comprehensive analysis of proteins expressed and released by Reed-Sternberg cells would assist in the discovery of potential biomarkers and improve our understanding of its pathogenesis. The subcellular proteome of the three cellular compartments from L428 and KMH2 Hodgkin lymphoma-derived cell lines were fractionated, and analyzed by reversephase liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Additionally, proteins released by Hodgkin lymphoma-derived L428 cells were extracted from serum-free culture media and analyzed. Peptide spectra were analyzed using TurboSEQUEST s against the UniProt protein database (5.26.05; 188 712 entries). A subset of the identified proteins was validated by Western blot analysis, immunofluorescence microscopy and immunohistochemistry. A total of 1945 proteins were identified with 785 from the cytosolic fraction, 305 from the membrane fraction, 441 from the nuclear fraction and 414 released proteins using a minimum of two peptide identifications per protein and an error rate of o5.0%. Identification of proteins from diverse functional groups reflected the functional complexity of the Reed-Sternberg proteome. Proteins with previously reported oncogenic function in other cancers and from signaling pathways implicated in Hodgkin lymphoma were identified. Selected proteins without previously demonstrated expression in Hodgkin lymphoma were validated by Western blot analysis (B-RAF, Erb-B3), immunofluorescence microscopy (Axin1, Tenascin-X, Mucin-2) and immunohistochemistry using a tissue microarray (BRAF, PIM1). This study represents the first comprehensive inventory of proteins expressed by Reed-Sternberg cells of Hodgkin lymphoma and demonstrates the utility of combining cellular subfractionation, protein precipitation, tandem mass spectrometry and bioinformatics analysis for comprehensive identification of proteins that may represent potential biomarkers of the disease.

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Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin's lymphoma

Cited by 58 publications

References 27 publications

JAK kinases overexpression promotes in vitro cell transformation

JAK kinases overexpression promotes in vitro cell transformation

Expression of Interleukin-9 in Nasal Natural Killer/T-Cell Lymphoma Cell Lines and Patients

Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed–Sternberg cells by LC-MS/MS

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