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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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Time-course analysis of Stat5b/5C.C7 and 5C.C7 mice. (A) CD8+ thymocyte numbers increase over time in Stat5b/5C.C7 double transgenic mice. Each point represents a single mouse. (B) CD4/CD8 profile of Stat5b/5C.C7 and 5C.C7 transgenic mice over time. Representative profiles are shown for the time points indicated (with total cellularity indicated above in parentheses). The 5C.C7 single transgenic mice either have significant loss of thymocytes over time (panels c and d) or an expansion of CD4+ cells with time (panels i and j), whereas the Stat5b/5C.C7 double transgenic mice have an expansion of CD8+ cells. (C) Anti-CD3 induced proliferation of total thymocytes. Each point represents a single mouse. (D) Shown is a dendogram resulting from unsupervised clustering of 6250 genes that were expressed “present” in any group. (E) Expression of genes that were found to be more highly expressed in Stat5b transgenic mice with lymphoma (see Fig. 4 C and online supplemental material), were also analyzed over time in 5C.C7 and in Stat5b/5C.C7 mice. In A and C, the 12-wk-old group includes all mice 12–13 wk old.
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fig7: Time-course analysis of Stat5b/5C.C7 and 5C.C7 mice. (A) CD8+ thymocyte numbers increase over time in Stat5b/5C.C7 double transgenic mice. Each point represents a single mouse. (B) CD4/CD8 profile of Stat5b/5C.C7 and 5C.C7 transgenic mice over time. Representative profiles are shown for the time points indicated (with total cellularity indicated above in parentheses). The 5C.C7 single transgenic mice either have significant loss of thymocytes over time (panels c and d) or an expansion of CD4+ cells with time (panels i and j), whereas the Stat5b/5C.C7 double transgenic mice have an expansion of CD8+ cells. (C) Anti-CD3 induced proliferation of total thymocytes. Each point represents a single mouse. (D) Shown is a dendogram resulting from unsupervised clustering of 6250 genes that were expressed “present” in any group. (E) Expression of genes that were found to be more highly expressed in Stat5b transgenic mice with lymphoma (see Fig. 4 C and online supplemental material), were also analyzed over time in 5C.C7 and in Stat5b/5C.C7 mice. In A and C, the 12-wk-old group includes all mice 12–13 wk old.

Mentions: Supplemental Fig. S1 shows RISs in the Stat5a/Stat5b genomic locus in two mice with AKXD Burkitt-like lymphoma. This suggests the oncogenic potential of RISs in either the Stat5a or Stat5b loci. Supplemental Table S1 shows a complete listing of genes from the microarray analyses presented in Fig. 4, B and C. Supplemental Table S2 shows a complete listing of genes from the microarray analyses presented in Fig. 7 E. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20021548/DC1.


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)

Time-course analysis of Stat5b/5C.C7 and 5C.C7 mice. (A) CD8+ thymocyte numbers increase over time in Stat5b/5C.C7 double transgenic mice. Each point represents a single mouse. (B) CD4/CD8 profile of Stat5b/5C.C7 and 5C.C7 transgenic mice over time. Representative profiles are shown for the time points indicated (with total cellularity indicated above in parentheses). The 5C.C7 single transgenic mice either have significant loss of thymocytes over time (panels c and d) or an expansion of CD4+ cells with time (panels i and j), whereas the Stat5b/5C.C7 double transgenic mice have an expansion of CD8+ cells. (C) Anti-CD3 induced proliferation of total thymocytes. Each point represents a single mouse. (D) Shown is a dendogram resulting from unsupervised clustering of 6250 genes that were expressed “present” in any group. (E) Expression of genes that were found to be more highly expressed in Stat5b transgenic mice with lymphoma (see Fig. 4 C and online supplemental material), were also analyzed over time in 5C.C7 and in Stat5b/5C.C7 mice. In A and C, the 12-wk-old group includes all mice 12–13 wk old.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196089&req=5

fig7: Time-course analysis of Stat5b/5C.C7 and 5C.C7 mice. (A) CD8+ thymocyte numbers increase over time in Stat5b/5C.C7 double transgenic mice. Each point represents a single mouse. (B) CD4/CD8 profile of Stat5b/5C.C7 and 5C.C7 transgenic mice over time. Representative profiles are shown for the time points indicated (with total cellularity indicated above in parentheses). The 5C.C7 single transgenic mice either have significant loss of thymocytes over time (panels c and d) or an expansion of CD4+ cells with time (panels i and j), whereas the Stat5b/5C.C7 double transgenic mice have an expansion of CD8+ cells. (C) Anti-CD3 induced proliferation of total thymocytes. Each point represents a single mouse. (D) Shown is a dendogram resulting from unsupervised clustering of 6250 genes that were expressed “present” in any group. (E) Expression of genes that were found to be more highly expressed in Stat5b transgenic mice with lymphoma (see Fig. 4 C and online supplemental material), were also analyzed over time in 5C.C7 and in Stat5b/5C.C7 mice. In A and C, the 12-wk-old group includes all mice 12–13 wk old.
Mentions: Supplemental Fig. S1 shows RISs in the Stat5a/Stat5b genomic locus in two mice with AKXD Burkitt-like lymphoma. This suggests the oncogenic potential of RISs in either the Stat5a or Stat5b loci. Supplemental Table S1 shows a complete listing of genes from the microarray analyses presented in Fig. 4, B and C. Supplemental Table S2 shows a complete listing of genes from the microarray analyses presented in Fig. 7 E. Online supplemental material is available at http://www.jem.org/cgi/content/full/jem.20021548/DC1.

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