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Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma.

Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA, Radonovich MF, Lee S, Jenkins NA, Copeland NG, Morse HC, Leonard WJ - J. Exp. Med. (2003)

Bottom Line: Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors.The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes.These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Heart and Blood Institute, National Cancer Institute, Bethesda, MD 20892-1674, USA.

ABSTRACT
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

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Stat5 transgenic mice are more prone to malignant transformation in the presence of a TCR transgene. (A) Mice that were heterozygous for the Stat5b and 5CC7 TCR transgenes (b and d) exhibited an increase in activated CD8+ T cells as compared with mice only carrying the 5CC7 transgene (a and c). CD4/CD8 (a and b), CD44/IL-2Rα (gated on CD4−/CD8− [DN], c and d), and Vβ3/Vα11 (e and f) profiles of mice that were heterozygous for the 5C.C7 TCR transgene and RAG2 (panels a, c, and e) and also for the Stat5b transgene (panels b, d, and f) are shown. (B) 5C.C7 TCR transgenic mice (panels a and d) and 5C.C7 TCR/Stat5b transgenic mice (panels b, c, e, and f) were immunized intraperitoneally with cytochrome c/CFA, and CD4/CD8 (panels a, b, and c) and CD44/IL-2Rα (gated on CD8+, panels d, e, and f) profiles were analyzed upon sacrifice 3 wk later. The mouse represented by panels b, e, and h had no evidence of lymphoma whereas the mouse represented by panels c, f, and i had an enlarged thymus consistent with lymphoblastic lymphoma. In A and B, total thymocyte numbers are shown in parentheses on the far right. (C) Age of diagnosis of lymphomas. Shown are Stat5b transgenic mice, not immunized or immunized with ovalbumin/CFA, and Stat5b/5C.C7 double transgenic mice that were either not immunized or immunized with cytochrome c/CFA. Each point represents a single mouse, and the median for each group is indicated by the horizontal bar. (D) Proliferation of thymocytes from mice that were heterozygous for both the Stat5b and 5CC7 TCR transgenes, with and without lymphoma, after incubation with cytochrome c (200 μg/ml) or 1 nM IL-7 for 72 h.
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fig6: Stat5 transgenic mice are more prone to malignant transformation in the presence of a TCR transgene. (A) Mice that were heterozygous for the Stat5b and 5CC7 TCR transgenes (b and d) exhibited an increase in activated CD8+ T cells as compared with mice only carrying the 5CC7 transgene (a and c). CD4/CD8 (a and b), CD44/IL-2Rα (gated on CD4−/CD8− [DN], c and d), and Vβ3/Vα11 (e and f) profiles of mice that were heterozygous for the 5C.C7 TCR transgene and RAG2 (panels a, c, and e) and also for the Stat5b transgene (panels b, d, and f) are shown. (B) 5C.C7 TCR transgenic mice (panels a and d) and 5C.C7 TCR/Stat5b transgenic mice (panels b, c, e, and f) were immunized intraperitoneally with cytochrome c/CFA, and CD4/CD8 (panels a, b, and c) and CD44/IL-2Rα (gated on CD8+, panels d, e, and f) profiles were analyzed upon sacrifice 3 wk later. The mouse represented by panels b, e, and h had no evidence of lymphoma whereas the mouse represented by panels c, f, and i had an enlarged thymus consistent with lymphoblastic lymphoma. In A and B, total thymocyte numbers are shown in parentheses on the far right. (C) Age of diagnosis of lymphomas. Shown are Stat5b transgenic mice, not immunized or immunized with ovalbumin/CFA, and Stat5b/5C.C7 double transgenic mice that were either not immunized or immunized with cytochrome c/CFA. Each point represents a single mouse, and the median for each group is indicated by the horizontal bar. (D) Proliferation of thymocytes from mice that were heterozygous for both the Stat5b and 5CC7 TCR transgenes, with and without lymphoma, after incubation with cytochrome c (200 μg/ml) or 1 nM IL-7 for 72 h.

Mentions: Because of the effect of anti-CD3 stimulation on the proliferation and activation of Stat5b transgenic thymocytes, we hypothesized that TCR activation might promote the growth and/or malignant transformation in Stat5b transgenic mice, consistent with a suggested role for immune receptor stimulation in certain lymphoid neoplasms (32, 33). In this regard, coexpression of a TCR transgene greatly augmented thymic CD8+ T cell development in the Stat5b transgenic mice. Remarkably, this occurred not only with the class I–restricted HY TCR trangene (unpublished data), but also with the 5C.C7 class II–restricted TCR trangene (Fig. 6 A, panels b versus a), even though class II restricted TCRs normally direct development in the CD4 pathway. Interestingly, expression of the 5C.C7 TCR transgene increased the percentage of DN1 cells (CD4−/CD8− double negative cells that are CD44hiIL-2Rα−; panel d versus c). After immunization, Stat5b/5C.C7 TCR transgenic mice had more CD8+ T cells than mice that expressed only the 5C.C7 TCR transgene (Fig. 6 B, panel b versus a), and there was an increase in the percentage of these CD8+ T cells that were activated (CD44hiIL-2Rα+; Fig. 6 B, panel e versus d). The CD8+ T cells were Vα11+/Vβ3+ (Fig. 6 B, panels g and h), confirming that their selection was via the cytochrome c-specific 5C.C7 TCR (34).


Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma.

Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA, Radonovich MF, Lee S, Jenkins NA, Copeland NG, Morse HC, Leonard WJ - J. Exp. Med. (2003)

Stat5 transgenic mice are more prone to malignant transformation in the presence of a TCR transgene. (A) Mice that were heterozygous for the Stat5b and 5CC7 TCR transgenes (b and d) exhibited an increase in activated CD8+ T cells as compared with mice only carrying the 5CC7 transgene (a and c). CD4/CD8 (a and b), CD44/IL-2Rα (gated on CD4−/CD8− [DN], c and d), and Vβ3/Vα11 (e and f) profiles of mice that were heterozygous for the 5C.C7 TCR transgene and RAG2 (panels a, c, and e) and also for the Stat5b transgene (panels b, d, and f) are shown. (B) 5C.C7 TCR transgenic mice (panels a and d) and 5C.C7 TCR/Stat5b transgenic mice (panels b, c, e, and f) were immunized intraperitoneally with cytochrome c/CFA, and CD4/CD8 (panels a, b, and c) and CD44/IL-2Rα (gated on CD8+, panels d, e, and f) profiles were analyzed upon sacrifice 3 wk later. The mouse represented by panels b, e, and h had no evidence of lymphoma whereas the mouse represented by panels c, f, and i had an enlarged thymus consistent with lymphoblastic lymphoma. In A and B, total thymocyte numbers are shown in parentheses on the far right. (C) Age of diagnosis of lymphomas. Shown are Stat5b transgenic mice, not immunized or immunized with ovalbumin/CFA, and Stat5b/5C.C7 double transgenic mice that were either not immunized or immunized with cytochrome c/CFA. Each point represents a single mouse, and the median for each group is indicated by the horizontal bar. (D) Proliferation of thymocytes from mice that were heterozygous for both the Stat5b and 5CC7 TCR transgenes, with and without lymphoma, after incubation with cytochrome c (200 μg/ml) or 1 nM IL-7 for 72 h.
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Related In: Results  -  Collection

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fig6: Stat5 transgenic mice are more prone to malignant transformation in the presence of a TCR transgene. (A) Mice that were heterozygous for the Stat5b and 5CC7 TCR transgenes (b and d) exhibited an increase in activated CD8+ T cells as compared with mice only carrying the 5CC7 transgene (a and c). CD4/CD8 (a and b), CD44/IL-2Rα (gated on CD4−/CD8− [DN], c and d), and Vβ3/Vα11 (e and f) profiles of mice that were heterozygous for the 5C.C7 TCR transgene and RAG2 (panels a, c, and e) and also for the Stat5b transgene (panels b, d, and f) are shown. (B) 5C.C7 TCR transgenic mice (panels a and d) and 5C.C7 TCR/Stat5b transgenic mice (panels b, c, e, and f) were immunized intraperitoneally with cytochrome c/CFA, and CD4/CD8 (panels a, b, and c) and CD44/IL-2Rα (gated on CD8+, panels d, e, and f) profiles were analyzed upon sacrifice 3 wk later. The mouse represented by panels b, e, and h had no evidence of lymphoma whereas the mouse represented by panels c, f, and i had an enlarged thymus consistent with lymphoblastic lymphoma. In A and B, total thymocyte numbers are shown in parentheses on the far right. (C) Age of diagnosis of lymphomas. Shown are Stat5b transgenic mice, not immunized or immunized with ovalbumin/CFA, and Stat5b/5C.C7 double transgenic mice that were either not immunized or immunized with cytochrome c/CFA. Each point represents a single mouse, and the median for each group is indicated by the horizontal bar. (D) Proliferation of thymocytes from mice that were heterozygous for both the Stat5b and 5CC7 TCR transgenes, with and without lymphoma, after incubation with cytochrome c (200 μg/ml) or 1 nM IL-7 for 72 h.
Mentions: Because of the effect of anti-CD3 stimulation on the proliferation and activation of Stat5b transgenic thymocytes, we hypothesized that TCR activation might promote the growth and/or malignant transformation in Stat5b transgenic mice, consistent with a suggested role for immune receptor stimulation in certain lymphoid neoplasms (32, 33). In this regard, coexpression of a TCR transgene greatly augmented thymic CD8+ T cell development in the Stat5b transgenic mice. Remarkably, this occurred not only with the class I–restricted HY TCR trangene (unpublished data), but also with the 5C.C7 class II–restricted TCR trangene (Fig. 6 A, panels b versus a), even though class II restricted TCRs normally direct development in the CD4 pathway. Interestingly, expression of the 5C.C7 TCR transgene increased the percentage of DN1 cells (CD4−/CD8− double negative cells that are CD44hiIL-2Rα−; panel d versus c). After immunization, Stat5b/5C.C7 TCR transgenic mice had more CD8+ T cells than mice that expressed only the 5C.C7 TCR transgene (Fig. 6 B, panel b versus a), and there was an increase in the percentage of these CD8+ T cells that were activated (CD44hiIL-2Rα+; Fig. 6 B, panel e versus d). The CD8+ T cells were Vα11+/Vβ3+ (Fig. 6 B, panels g and h), confirming that their selection was via the cytochrome c-specific 5C.C7 TCR (34).

Bottom Line: Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors.The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes.These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Heart and Blood Institute, National Cancer Institute, Bethesda, MD 20892-1674, USA.

ABSTRACT
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

Show MeSH
Related in: MedlinePlus