Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells

Qiu, Lin; Lai, Raymond; Lin, Qinlu; Lau, Esther; Thomazy, David; Calame, Daniel G.; Ford, R.; Kwak, Larry W.; Kirken, Robert A.; Amin, Hesham M.

doi:10.1182/blood-2006-04-020305

Cited by 74 publications

(60 citation statements)

References 56 publications

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“…52 In addition, we recently identified the autocrine release of IL-9 by ALK ϩ ALCL cells as an upstream modulator of the Jak3/Stat3 signaling system in these cells. 57 Consistent with the selective inhibition of Jak3, an anti-IL-9 neutralizing antibody was shown to downregulate phosphorylated Jak3 and Stat3 and to decrease NPM-ALK kinase activity. 57 It is possible that the interactions between Jak3 and NPM-ALK are similar to the recently described interactions between Src and each of NPM-ALK and Bcr-Abl.…”

Section: Oncogenic Molecules That Interact With Npm-alk Jak/statmentioning

confidence: 83%

“…57 Consistent with the selective inhibition of Jak3, an anti-IL-9 neutralizing antibody was shown to downregulate phosphorylated Jak3 and Stat3 and to decrease NPM-ALK kinase activity. 57 It is possible that the interactions between Jak3 and NPM-ALK are similar to the recently described interactions between Src and each of NPM-ALK and Bcr-Abl. Cussac et al 58 Another mechanism of Stat3 constitutive activation in ALK ϩ ALCL occurs via downregulation of SH2 domain-containing protein tyrosine phosphatase-1 (Shp1), which is a nontransmembrane tyrosine phosphatase predominantly expressed in hematopoietic cells.…”

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confidence: 83%

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Pathobiology of ALK+ anaplastic large-cell lymphoma

Amin

Lai

2007

Blood

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Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALKexpressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK. IntroductionAnaplastic large-cell lymphoma (ALCL) is a relatively uncommon tumor. It was first recognized by Stein et al 1 in 1985, who reported the consistent expression of the Ki-1 antigen (later designated CD30) in tumors with frequent cohesive proliferation of large pleomorphic cells. Most of these tumors were labeled "histiocytic malignancies." 1 The Ki-1 monoclonal antibody was originally described by the same group and was used to identify a novel antigen in the Hodgkin lymphoma cell line L428. 2 Subsequent immunophenotyping and gene rearrangement studies showed that the vast majority of ALCL tumors are derived from lymphoid cells of T or null immunophenotype. 3 Histologically, several ALCL variants have been described. Of these variants, the common, lymphohistiocytic, and small-cell are the most frequently encountered. The "horseshoe" or "wreath" cell is considered the cytologic hallmark of this disease. 4 ALCL occurs as 2 distinct clinical entities, as a widespread systemic disease, or as a localized cutaneous disease. Systemic ALCL comprises 2% to 8% of non-Hodgkin lymphomas in adults and 10% to 15% of these lymphomas in children. 5 The frequency of ALCL increases to 30% to 40% of non-Hodgkin lymphomas in children when only cases with large-cell morphology are included. ALKThe recognition of t(2;5)(p23;q35) established the molecular definition of a subset of ALCL tumors that harbors this translocation. [6][7][8] In 1994, 2 independent groups cloned the genes involved in this translocation and illustrated the fusion of the nucleophosmin (NPM) gene on chromosome 5q35 to the previously unidentified gene anaplastic lymphoma kinase (ALK) gene on 2p23. 9,10 This chromosomal t...

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Section: Oncogenic Molecules That Interact With Npm-alk Jak/statmentioning

confidence: 83%

mentioning

confidence: 83%

Pathobiology of ALK+ anaplastic large-cell lymphoma

Amin

Lai

2007

Blood

Self Cite

236

173

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“…Finally, treatment with a high-dose of methylprednisolone was demonstrated to reduce serum IL-9 levels and the percentages of CD4 + IL-9 + T cells, indicating that IL-9 and CD4 + IL-9 + T cells are involved in the inflammatory process of SLE. The use of IL-9-specific antibodies in the treatment of several conditions, such as EAE (13), collagen-induced arthritis (14), transplantation (22), chronic active EBV infection (23) and human anaplastic large-cell lymphoma cells (24), has been previously implemented. Targeting IL-9 in human SLE could be a promising approach in the future.…”

Section: Discussionmentioning

confidence: 99%

Increased interleukin-9 and CD4+IL-9+ T cells in patients with systemic lupus erythematosus

Ouyang

Shi

Liu

et al. 2013

Molecular Medicine Reports

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Abstract. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin affecting all the organ systems. Apart from genetic and environmental factors, autoantibody and immune complex deposition as well as cytokine imbalances contribute to immune dysfunction. Interleukin-9 (IL-9) is a T cell-derived factor preferentially expressed by CD4 + T cells and it has been characterized in human and murine systems. IL-9 targets cells of the lymphoid, myeloid and mast cell lineages, and is likely to contribute to the development of allergic and autoimmune diseases such as asthma, arthritis, multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Nevertheless, until recently there have been no studies on its role in SLE in humans. In the present study, the mRNA and serum IL-9 levels in the peripheral blood of SLE patients and healthy controls were assessed using real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Flow cytometry was used to analyze the percentages of CD4 + IL-9 + T cells in SLE patients. Moreover, differences between the groups and the effect of glucocorticoids were analyzed. The results showed that the plasma concentration and mRNA levels of IL-9 were significantly elevated in SLE patients compared with the healthy controls. The percentages of CD4 + IL-9 + T cells were also increased in SLE patients. In addition, serum IL-9 levels and the percentages of CD4 + IL-9 + T cells were correlated with the SLE disease activity index (SLEDAI). Additionally, the percentages of CD4 + IL-9 + T cells and serum IL-9 levels in 8 untreated active SLE patients were decreased at 1, 2 and 3 weeks after treatment with methylprednisolone. In conclusion, we provide evidence that IL-9 is increased in SLE patients. Moreover, it is described for the first time that high expression of IL-9 levels and the percentages of CD4 + IL-9 + T cells correlate with disease activity and severity. This suggests an important role of IL-9 in the pathogenesis of SLE.

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“…Immunohistochemical staining was performed on formalin-fixed paraffin-embedded sections obtained from cell-blocks of cell lines or the human tumors using a DakoCytomation kit (Carpinteria, CA, USA) as previously described. 22,23,33,34 Additional information on immuno histochemical staining is given in the Online Suppl ementary Methods.…”

Section: Polymerase Chain Reaction Analyses Antigen Density and Westmentioning

confidence: 99%

Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

Vishwamitra¹,

Shi²,

Wilson³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundType I insulin-like growth factor receptor (IGF-IR) tyrosine kinase induces significant oncogenic effects. Strategies to block IGF-IR signaling are being tested in clinical trials that include patients with aggressive solid malignancies. Mantle cell lymphoma is a B-cell neoplasm with poor prognosis and a tendency to develop resistance. The expression and potential significance of IGF-IR in mantle cell lymphoma are not known. Design and MethodsWe used reverse transcriptase polymerase chain reaction, quantitative real-time polymerase chain reaction, immunoprecipitation, western blotting, flow cytometry, and immunohistochemistry to analyze the expression of IGF-IR mRNA, and IGF-IR and pIGF-IR proteins in mantle cell lymphoma cell lines and patients' specimens. Selective and specific blockade of IGF-IR was achieved using picropodophyllin and short-interfering RNA, respectively. Cell viability, apoptosis, cell cycle, cellular morphology, cell proliferation, and target proteins were then analyzed. ResultsWe detected the expression of IGF-IR and pIGF-IR in mantle cell lymphoma cell lines. Notably, IGF-IR molecules/cell were markedly increased in mantle cell lymphoma cell lines compared with human B-lymphocytes. IGF-IR and pIGF-IR were also detected in 78% and 74%, respectively, of 23 primary mantle cell lymphoma specimens. Treatment of serum-deprived mantle cell lymphoma cell lines with IGF-I salvaged these cells from apoptosis. Selective inhibition of IGF-IR by picropodophyllin decreased the viability and proliferation of mantle cell lymphoma cell lines, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase-3, caspase-8, caspase-9, and PARP cleavage, cytochrome c release, up-regulation of cyclin B1, and down-regulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. Similar results were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyllin decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR. ConclusionsIGF-IR is up-regulated and frequently activated in mantle cell lymphoma. Our data suggest that IGF-IR could be a molecular target for the treatment of mantle cell lymphoma. Haematologica 2011;96(6):871-880. doi:10.3324/haematol.2010 Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

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Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells

Cited by 74 publications

References 56 publications

Pathobiology of ALK+ anaplastic large-cell lymphoma

Pathobiology of ALK+ anaplastic large-cell lymphoma

Increased interleukin-9 and CD4+IL-9+ T cells in patients with systemic lupus erythematosus

Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma

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