Interleukin‐9 stimulates <i>in vitro</i> growth of mouse thymic lymphomas

Vink, Anne; Renauld, Jean‐Christophe; Warnier, Guy; Snick, Jacques Van

doi:10.1002/eji.1830230523

Cited by 53 publications

(28 citation statements)

References 30 publications

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“…These findings extend previous observations defining the importance of IL-6 in the classical model of pristane-induced peritoneal PCT in conventional C mice (26)(27)(28). They also complement earlier studies showing that C mice homozygous for an IL-6-null allele are resistant to peritoneal PCT induced by pristane (29) and accelerated peritoneal PCT induced by a Myc͞Raf retrovirus plus pristane (30).…”

Section: Discussionsupporting

confidence: 90%

IL-6 transgenic mouse model for extraosseous plasmacytoma

Kovalchuk

Kim

Park

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

123

110

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Plasma cell neoplasms in humans comprise plasma cell myeloma, otherwise known as multiple myeloma, Ig deposition and heavy chain diseases, and plasmacytoma (PCT). A subset of PCT, designated extramedullary PCT, is distinguished from multiple myeloma and solitary PCT of bone by its distribution among various tissue sites but not the bone marrow. Extramedullary (extraosseus) PCT are rare spontaneous neoplasms of mice but are readily induced in a susceptible strain, BALB͞c, by treatment with pristane. The tumors develop in peritoneal granulomas and are characterized by Myc-activating T(12;15) chromosomal translocations and, most frequently, by secretion of IgA. A uniting feature of human and mouse plasma cell neoplasms is the critical role played by IL-6, a B cell growth, differentiation, and survival factor. To directly test the contribution of IL-6 to PCT development, we generated BALB͞c mice carrying a widely expressed IL-6 transgene. All mice exhibited lymphoproliferation and plasmacytosis. By 18 months of age, over half developed readily transplantable PCT in lymph nodes, Peyer's patches, and sometimes spleen. These neoplasms also had T(12;15) translocations, but remarkably, none expressed IgA. Unexpectedly, Ϸ30% of the mice developed follicular and diffuse large cell B cell lymphomas that often coexisted with PCT. These findings provide a unique model of extramedullary PCT for studies on pathogenesis and treatment and suggest a previously unappreciated role for IL-6 in the genesis of germinal center-derived lymphomas.

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Section: Discussionsupporting

confidence: 90%

IL-6 transgenic mouse model for extraosseous plasmacytoma

Kovalchuk

Kim

Park

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

123

110

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“…Inhibition of BW-h9R proliferation by hIL-9 contrasted with the previously described growth-promoting activity of IL-9 for a number of factor-dependent cell lines (28,35,36). To determine whether transfection of the hIL-9R could also confer IL-9-dependent proliferation, we transfected the IL-3-dependent pro-B cell line Ba/F3, which has been successfully used by several groups for similar receptor studies (4,7,24,34).…”

Section: Resultsmentioning

confidence: 95%

A Single Tyrosine of the Interleukin-9 (IL-9) Receptor Is Required for STAT Activation, Antiapoptotic Activity, and Growth Regulation by IL-9

Demoulin

Uyttenhove

Roost

et al. 1996

Molecular and Cellular Biology

173

179

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Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor ␥ chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines of other receptors activating STAT3 and STAT5 were observed. Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses.Interleukin-9 (IL-9) is a multifunctional cytokine secreted by activated T cells (35). Biological targets for IL-9 include mast cells, B lymphocytes, T-cell clones, hematopoietic progenitors, and immature neuronal cell lines (27,28). In addition, IL-9 seems to be involved in both human and murine tumorigenesis. In vitro, IL-9 induces proliferation of T-cell lymphomas and protects them against dexamethasone-induced apoptosis (30). In vivo, IL-9 transgenic mice spontaneously develop lymphomas and are highly susceptible to chemical mutagenesis (29). Finally, the existence of an IL-9-mediated autocrine loop in Hodgkin's disease has been suggested (9, 21). IL-9 activities are mediated through a receptor that belongs to the hematopoietin receptor superfamily (26). Like other members of this family, the cytoplasmic part of the human IL-9 receptor (hIL-9R) does not bear any consensus sequence for tyrosine kinase domains and was only characterized by a high percentage of proline and serine residues. Several observations have stressed similarities between IL-9R and IL-2R. The intracellular juxtamembrane region of hIL-9R, which contains the box 1 consensus sequence (24), shows a significant homology with the IL-2 receptor ␤ chain (IL-2R␤). Moreover, although hIL-9R is sufficient for high-affinity binding of IL-9, it was recently shown to interact with the IL-2R ␥ chain (␥ c ) (17, 31). On the basis of this observation, IL-9 was associated with the IL-2 cytokine family, which includes IL-2, IL-4, IL-7, and IL-15.These cytokines share c...

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“…IL-9 seems to be involved in both human and murine tumorigenesis. In vitro, IL-9 induced proliferation of T-cell lymphomas and protects them against dexamethasone-induced apoptosis (Vink et al, 1993;Renauld et al, 1995). In vivo, IL-9 transgenic mice spontaneously developed precursor T-lymphoblastic lymphomas (Renauld et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of NPM–ALK induces different types of malignant lymphomas in IL-9 transgenic mice

et al. 2003

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Anaplastic large-cell lymphoma (ALCL) comprises approximately 25% of all non-Hodgkin lymphomas (NHL) in children and young adults, and up to 15% of high-grade NHL in older patients. Over 50% of these tumours carry the translocation t(2;5)(p23;q35). The result of this translocation is the fusion of the nucleophosmin (NPM) gene to the anaplastic lymphoma kinase (ALK) gene. The resulting hybrid protein contains the ALK catalytic domain that consequently confers transforming potential, which contributes to the pathogenesis of ALCL. To further analyse the transforming activity in an animal model, a cDNA encoding the protein product, NPM-ALK, was inserted into the retrovirus vector pLXSN and transduced into mouse bone marrow progenitors. These cells were subsequently used in a bone marrow transplant with the aim of reconstituting the haematopoietic compartments of lethally irradiated recipients. IL-9 transgenic mice were chosen as the animal model system, because dysregulated expression of the IL-9 gene in transgenic mice results in the sporadic development of spontaneous thymic lymphomas. Moreover, IL-9 is known to be expressed in cases of human ALCL. We used 15 IL-9 transgenic mice and eight corresponding wild-type mice (FVB/N) and transplanted them with NPM/ALK infected bone marrow cells. Eight IL-9 transgenic mice, serving as a control group, received pLXSN (vector only)-infected marrow. Reconstituted mice developed NPM-ALK-positive lymphomas, including lymphoblastic lymphomas of Tcell type (T-LB), mature and immature plasmacytoma (PC), and plasmoblastic/anaplastic diffuse large-B-cell lymphoma after about 19-20 weeks. The combined overexpression of NPM-ALK and IL-9 led to the transformation of murine lymphoid cells with accelerated and enhanced development of T-LB in 46% of the mice, which only very rarely occurs in IL-9 transgenic mice only. Of the 15 animals, five (33%) developed plasmacytic/plasmoblastic neoplasms, of which the most aggressive tumours share many features with anaplastic/plasmoblastic diffuse large-B-cell lymphoma on the basis of morphology, a characteristic growth pattern and ALK expression.

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Interleukin‐9 stimulates in vitro growth of mouse thymic lymphomas

Cited by 53 publications

References 30 publications

IL-6 transgenic mouse model for extraosseous plasmacytoma

IL-6 transgenic mouse model for extraosseous plasmacytoma

A Single Tyrosine of the Interleukin-9 (IL-9) Receptor Is Required for STAT Activation, Antiapoptotic Activity, and Growth Regulation by IL-9

Overexpression of NPM–ALK induces different types of malignant lymphomas in IL-9 transgenic mice

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