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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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Related in: MedlinePlus

Oligonucleotide (GeneChip®) microarray analysis indicating that the lymphomas are of thymic origin. (A) Shown is a dendogram corresponding to 4372 genes whose expression was detected in all groups (WTS, TGS, CD8WTS, CD8TGS, WTT, TGT, ONCOS, ONCOT). The “Thymic” and “Splenic” clusters refer to samples whose expression patterns were most similar to those found in normal thymus and spleen, respectively (i.e., they “coclustered”). Note that the pattern observed for CD8+ T cell enriched splenocytes was similar to that observed in total splenocytes. The mice with lymphomas are designated as in Table I. (B) A selection of genes that were similarly expressed in the lymphomas and thymic tissue. (C) Genes that were more highly expressed (>1.4-fold increased) in lymphomas than in any of the WT or TG tissue samples. Green squares correspond to genes with relatively low level of expression and red squares to genes with relatively high level of expression (e.g., in one of the TGT samples [second from the right] fewer genes were highly expressed). The raw data and a complete list of the genes will be available at www.nhlbi.nih.gov/labs/supplements.
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fig4: Oligonucleotide (GeneChip®) microarray analysis indicating that the lymphomas are of thymic origin. (A) Shown is a dendogram corresponding to 4372 genes whose expression was detected in all groups (WTS, TGS, CD8WTS, CD8TGS, WTT, TGT, ONCOS, ONCOT). The “Thymic” and “Splenic” clusters refer to samples whose expression patterns were most similar to those found in normal thymus and spleen, respectively (i.e., they “coclustered”). Note that the pattern observed for CD8+ T cell enriched splenocytes was similar to that observed in total splenocytes. The mice with lymphomas are designated as in Table I. (B) A selection of genes that were similarly expressed in the lymphomas and thymic tissue. (C) Genes that were more highly expressed (>1.4-fold increased) in lymphomas than in any of the WT or TG tissue samples. Green squares correspond to genes with relatively low level of expression and red squares to genes with relatively high level of expression (e.g., in one of the TGT samples [second from the right] fewer genes were highly expressed). The raw data and a complete list of the genes will be available at www.nhlbi.nih.gov/labs/supplements.

Mentions: To examine gene expression patterns over time, 5C.C7 TCR transgenic mice, with and without the Stat5b transgene, were killed at 2, 3, 6, 12 or 13 wk of age. CD8+ thymocytes were enriched using CD4 paramagnetic beads and an autoMACS (Miltenyi Biotec). RNA was extracted and hybridized to U75A GeneChips®, as described above, and data were analyzed using hierarchical clustering (18). Analysis was performed using unsupervised hierarchical clustering (as above) for 6250 genes whose expression was detected (“present”; see online supplemental material) in any of four groups (5C.C7 single transgenic [group 1], Stat5b/5C.C7 double transgenic 2–3 wk old [group 2], Stat5b/5C.C7 double transgenic 6–8 weeks old [group 3], Stat5b/5C.C7 double transgenic 12–13 wk old [group 4]) were presented as a dendogram. In addition, genes that were found to be increased in lymphomas in Stat5b transgenic mice (see Fig. 4 C) were examined over time in 5C.C7 and Stat5b/5C.C7 mice.


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)

Oligonucleotide (GeneChip®) microarray analysis indicating that the lymphomas are of thymic origin. (A) Shown is a dendogram corresponding to 4372 genes whose expression was detected in all groups (WTS, TGS, CD8WTS, CD8TGS, WTT, TGT, ONCOS, ONCOT). The “Thymic” and “Splenic” clusters refer to samples whose expression patterns were most similar to those found in normal thymus and spleen, respectively (i.e., they “coclustered”). Note that the pattern observed for CD8+ T cell enriched splenocytes was similar to that observed in total splenocytes. The mice with lymphomas are designated as in Table I. (B) A selection of genes that were similarly expressed in the lymphomas and thymic tissue. (C) Genes that were more highly expressed (>1.4-fold increased) in lymphomas than in any of the WT or TG tissue samples. Green squares correspond to genes with relatively low level of expression and red squares to genes with relatively high level of expression (e.g., in one of the TGT samples [second from the right] fewer genes were highly expressed). The raw data and a complete list of the genes will be available at www.nhlbi.nih.gov/labs/supplements.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Oligonucleotide (GeneChip®) microarray analysis indicating that the lymphomas are of thymic origin. (A) Shown is a dendogram corresponding to 4372 genes whose expression was detected in all groups (WTS, TGS, CD8WTS, CD8TGS, WTT, TGT, ONCOS, ONCOT). The “Thymic” and “Splenic” clusters refer to samples whose expression patterns were most similar to those found in normal thymus and spleen, respectively (i.e., they “coclustered”). Note that the pattern observed for CD8+ T cell enriched splenocytes was similar to that observed in total splenocytes. The mice with lymphomas are designated as in Table I. (B) A selection of genes that were similarly expressed in the lymphomas and thymic tissue. (C) Genes that were more highly expressed (>1.4-fold increased) in lymphomas than in any of the WT or TG tissue samples. Green squares correspond to genes with relatively low level of expression and red squares to genes with relatively high level of expression (e.g., in one of the TGT samples [second from the right] fewer genes were highly expressed). The raw data and a complete list of the genes will be available at www.nhlbi.nih.gov/labs/supplements.
Mentions: To examine gene expression patterns over time, 5C.C7 TCR transgenic mice, with and without the Stat5b transgene, were killed at 2, 3, 6, 12 or 13 wk of age. CD8+ thymocytes were enriched using CD4 paramagnetic beads and an autoMACS (Miltenyi Biotec). RNA was extracted and hybridized to U75A GeneChips®, as described above, and data were analyzed using hierarchical clustering (18). Analysis was performed using unsupervised hierarchical clustering (as above) for 6250 genes whose expression was detected (“present”; see online supplemental material) in any of four groups (5C.C7 single transgenic [group 1], Stat5b/5C.C7 double transgenic 2–3 wk old [group 2], Stat5b/5C.C7 double transgenic 6–8 weeks old [group 3], Stat5b/5C.C7 double transgenic 12–13 wk old [group 4]) were presented as a dendogram. In addition, genes that were found to be increased in lymphomas in Stat5b transgenic mice (see Fig. 4 C) were examined over time in 5C.C7 and Stat5b/5C.C7 mice.

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