Autonomous growth and tumorigenicity induced by P40/interleukin 9 cDNA transfection of a mouse P40-dependent T cell line.

Uyttenhove, Catherine; Druez, C; Renauld, Jean‐Christophe; Hérin, Michel; Noel, H R; Snick, Jacques Van

doi:10.1084/jem.173.2.519

Cited by 55 publications

(19 citation statements)

References 16 publications

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“…36 Despite the lack of significant effects on freshly isolated T cells, 24,37 IL-9 induces significant proliferative effects on stimulated T cells. 23,24 Nonetheless, Renauld et al showed that only 7% of IL-9 transgenic mice develop T-cell thymic lymphomas. 38 Importantly, a subcarcinogenic dose of N-methyl-N-nitrosourea induced thymic lymphomas in all of the treated IL-9 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

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

Qiu

Lai

Lin

et al. 2006

Blood

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The aberrant fusion protein NPM-ALK plays an important pathogenetic role in ALK ؉ anaplastic large-cell lymphoma (ALCL). We previously demonstrated that Jak3 potentiates the activity of NPM-ALK. Jak3 activation is restricted to interleukins that recruit the common ␥ chain (␥c) receptor, including IL-9. NPM-ALK was previously shown to promote widespread lymphomas in IL-9 transgenic mice by unknown mechanisms. We hypothesized that IL-9 plays an important role in ALK ؉ ALCL via Jak3 activation. Our studies demonstrate the expression of IL-9R␣ and IL-9 in 3 ALK ؉ ALCL-cell lines and 75% and 83% of primary tumors, respectively. IL-9 was detected in serum-free culture medium harvested from ALK ؉ ALCL-cell lines, supporting autocrine release of IL-9. Treatment of these cells with an anti-IL-9-neutralizing antibody decreased pJak3 and its kinase activity, along with pStat3 and ALK kinase activity. These effects were associated with decreased cell proliferation and colony formation in soft agar and cell-cycle arrest.Evidence suggests that cell-cycle arrest can be attributed to up-regulation of p21 and down-regulation of Pim-1. Our results illustrate that IL-9/Jak3 signaling plays a significant role in the pathogenesis of ALK ؉ ALCL and that it represents a potential therapeutic target for treating patients with ALK ؉ ALCL. (Blood. 2006; 108:2407-2415)

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Section: Discussionmentioning

confidence: 99%

“…IL-9 is known to induce proliferation and antiapoptotic effects in T cells. [23][24][25] Previous studies showed that enforced expression of NPM-ALK in IL-9 transgenic mice induces widespread lymphoma. 26 The mechanism by which IL-9 promotes NPM-ALK activity is not known.…”

Section: Introductionmentioning

confidence: 99%

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

Qiu

Lai

Lin

et al. 2006

Blood

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“…21 The progressive deregulation undergone by T cells during acquisition of IL-9 responsiveness is somewhat reminiscent of the multistep process leading to cell transformation. 22,23 Furthermore, the IL-9-responsive TS1 cell line could spontaneously give rise to growth factor (GF)-independent clones that were tumorigenic in vivo. 24 Even though there was no autocrine cytokine production in the supernatants of these GF-independent clones, they showed constitutive phosphorylation of JAK1, JAK3, STAT3, and STAT5 comparable to those induced by IL-9 stimulation in parental TS1 cells.…”

Section: W515kmentioning

confidence: 99%

Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors

Springuel

Hornakova

Losdyck

et al. 2014

Blood

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Key Points• Cells transformed by activating JAK1 mutations become resistant to JAK inhibitor by acquiring activating mutations in JAK3 and vice versa.• JAK1 and JAK3 mutants cooperatively activate STAT transcription factors.The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors. (Blood. 2014;124(26):3924-3931)

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“…The murine cell line TS1G6 was reported in detail earlier (Uyttenhove et al, 1991). In brief, an intraabdominal (IAb)-restricted, CD3ϩ, CD4ϩ T helper cell clone (TS1) derived from a C57Bl/6 mouse and specific for human keyhole limpet hemocyanin (KLH) was cultured without antigen and feeder cells, but in the presence of IL-9.…”

Section: Morphological and Immunohistochemical Characterization Of Tsmentioning

confidence: 99%

An Animal Model for Anaplastic Large Cell Lymphoma in the Immunocompetent Syngeneic C57Bl/6 Mouse

Bittner

Feller

Renauld

et al. 2000

Laboratory Investigation

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SUMMARY:We report on the analysis of a murine anaplastic lymphoid cell line TS1G6, established recently by interleukin (IL)-9 transfection. TS1G6 revealed a highly characteristic pattern of large anaplastic cells with mononuclear, binuclear, or multinuclear cells resembling Hodgkin (H) or Sternberg-Reed (SR) cells. This cell line is tumorigenous after injection of as few as 10 4 lymphoma cells into nude or immunocompetent C57Bl/6 mice and leads to death from progressive disease of all treated animals within a few weeks. The histological analysis of these tumors revealed a diffuse large cell malignant lymphoma that is morphologically almost identical to human anaplastic large cell lymphoma (ALCL). The lymphoma cells did not show overexpression of the anaplastic lymphoma kinase (ALK) gene, which is found in about 50% of the cases of human ALCL. Thus, this model may be an animal model for an important subset of human ALCL. The cytokine profile, which is of the T helper 2 type, showed strong parallels to the human lymphoma counterpart. Mice suffering from such lymphomas could not be cured with a regimen using high dose cyclophosphamide similar to many ALCL patients. Such an animal model for ALCL has not yet been recognized, but may provide the basis for investigating new antitumor immunotherapies in a fully immunocompetent host . (Lab Invest 2000, 80:1523-1531.

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Autonomous growth and tumorigenicity induced by P40/interleukin 9 cDNA transfection of a mouse P40-dependent T cell line.

Cited by 55 publications

References 16 publications

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

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

Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors

An Animal Model for Anaplastic Large Cell Lymphoma in the Immunocompetent Syngeneic C57Bl/6 Mouse

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