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RNA-seq data from C57BL/6N, cS5Ahi and cS5Alo CD8+ murine T-cells isolated from lymph nodes

ABSTRACT: Recurrent gain-of-function mutations in the transcription factor STAT5B, but not STAT5A, have been detected in mature T- and NK-cell neoplasms. No targeted therapy exists for these heterogeneous and often aggressive diseases. Also, the bystander or balancer role for STAT5A versus STAT5B is unclear. Given this and the shortage of high-fidelity models for peripheral T-cell lymphomas (PTCL), we investigated here whether graded expression of a gain-of-function STAT5A variant produces tumorous T-cell expansions. To mimic STAT5 activity we expressed a hyperactive STAT5A variant at low or high levels in the hematopoietic system of transgenic mice (termed cS5Alo and cS5Ahi). Only cS5Ahi-mice developed a lethal disease resembling human PTCL with full penetrance, characterized by massive expansion of CD8+ T-cells and by destructive organ-infiltration. Neoplastic cS5Ahi-T-cells were cytokine-hypersensitive, showed cytotoxic features, and revealed activated memory CD8+ T-lymphocyte characteristics. Histopathology analysis and mRNA expression profiles of cS5Ahi tumors revealed close correlation with distinct human PTCL subtypes, similar to the hSTAT5BN642H mouse model expressing the most frequent STAT5B mutation. We found pronounced STAT5 expression and activity in patient samples of different PTCL subsets. Clinical-grade JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death in murine and human PTCL cell lines and Ruxolitinib (JAK1/2) ameliorated the disease in cS5Ahi mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE124102 | GEO | 2020/02/24

REPOSITORIES: GEO

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Activating Mutation in STAT5 Is Sufficient To Drive PTCL peripheral T-Cell Lymphoma (PTCL)

Project description:Recurrent gain-of-function mutations in the transcription factor STAT5 have been detected in PTCL, an aggressive, heterogeneous disease, for which currently no targeted therapy exists. Here we investigated whether constitutive activation of STAT5 suffices to drive PTCL and whether inhibition of the JAK/STAT pathway offers a novel therapeutic opportunity in this disease. We found pronounced STAT5 expression and activity in patients from different PTCL subsets. To mimic high STAT5 activity we expressed a hyperactive STAT5A variant (termed vcS5) in the hematopoietic lineage in transgenic mice. vcS5-transgenic animals developed a lethal PTCL-like disease with full penetrance, characterized by massive expansion of CD8+ T-cells and destructive organ-infiltration. Adoptive transfer of vcS5-expressing CD8+ T-cell rapidly induced the disease in immunocompetent recipient mice. Neoplastic vcS5-T-cells displayed cytokine-hypersensitivity and showed activated, memory CD8+ T-lymphocyte characteristics. Histo-pathological analysis as well as mRNA expression profiles of vcS5 mice was closely correlated with distinct human lymphoma subtypes, including PTCL. Treatment of murine and human PTCL cell lines with the clinical JAK inhibitor Ruxolitinib or a selective STAT5 SH2 domain inhibitor induced cell death. Thus, our results demonstrate that enhanced STAT5 signaling drives PTCL development and suggest inhibition of the JAK/STAT5 pathway as a valuable therapeutic option for patients suffering from these aggressive lymphomas.

2017-10-18 | GSE74176 | GEO

Essential role of STAT5 tyrosine phosphorylation in vivo

Project description:STAT5 proteins are vital for lymphocyte development and function. Tyrosine phosphorylation of a C-terminal tyrosine is the key event in cytokine activation of STAT5A and STAT5B. However, the role of STAT5 tyrosine phosphorylation has not been assessed in vivo. Here we generated Stat5a and Stat5b tyrosine mutant knock-in (KI) mice and found that these animals had greatly reduced CD8+ T cell numbers. These cells exhibited profoundly diminished proliferation in response to IL-2, correlating with greatly reduced IL-2-induced pRB and a block in the G1-->S phase transition. The mutant cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2R-beta and IL-2R-gamma. Our findings highlight that the tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling and elucidate the molecular basis for achieving an optimal mitogenic effect of IL-2 on CD8+ T cells.

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Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

Project description:Two highly conserved transcription factors STAT5A and STAT5B play an identical role in the intracellular signaling pathway upon cytokine stimulation, while gene deletion experiments have revealed separable and overlapping functions of STAT5. This questions whether the phenotypic differences in the organ development observed in the individual knockout mice result from isoform-specific functions or quantitative differences in the expression levels of each STAT5 isoform among tissues. To elucidate the redundancy and isoform-specificity of STAT5 for development at molecular levels, mice carrying only a single allele of either Stat5a or Stat5b were generated. Both of these mice overcame the lethal anemia observed in Stat5ab-null mice, indicating that development of erythroid cell lineage was totally dependent on the dosage of STAT5. The blocked progression of B cell lineage at the pre-pro B cell stage in Stat5ab-/- mice was rescued in the presence of a single allele of either Stat5a or Stat5b, while the number of total B220+ cells in bone marrow was smaller in Stat5abnull/Stat5b- mice than Stat5abnull/Stat5a- mice. The paucity of alveolar progenitor cells in the Stat5ab-null mammary epithelium was rescued by a single allele of either Stat5a but not Stat5b, suggesting cell-type dependent isoform-specific function. Genome-wide gene expression analyses revealed that different steps of cell lineage progression require different gene sets which expression requires the different isoform of STAT5 in a dose-dependent manner in the mammary epithelium. Taken together, this study demonstrates that dose-dependent isoform specificity of STAT5A and STAT5B controls progression and differentiation of each cell lineage. Six days after observation of a plug, mammary tissues from three of each Stat5a-/- mice, Stat5ab+/null mice, Stat5abnull/Stat5b- and Stat5abnull/Stat5a- mice were collected, frozen in liquid nitrogen, and stored at -70 °C

2012-04-30 | E-GEOD-29045 | biostudies-arrayexpress

Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function (ChIP-Seq and RNA-Seq)

Project description:Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a and Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined consensus motifs for dimers versus tetramers. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable, indicating that STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced proliferation and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function. Genome-wide mapping of STAT5A,STAT5B binding in mouse WT and DKI T cells (cultured with or without IL-2 for 1 hr) was conducted. RNA-Seq is conducted in mouse CD8+ T cells (WT and DKI, non-treated or treated with IL-2/IL-15 for 4 hr, 24 hr, 48 hr and 72 hr)

2012-04-25 | E-GEOD-36882 | biostudies-arrayexpress

Essential role of STAT5 tyrosine phosphorylation in vivo

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Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and its mitogenic action

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Genetic modification of STAT5 levels reveals dose-dependent and isoform-specific requirement for cell lineage progression and differentiation.

2012-05-01 | GSE29045 | GEO

Identification of Stat5 Target Genes by siRNA-mediated knockdown

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2008-06-23 | GSE10389 | GEO

Impact of STAT5 dosage and binding location on genetic and biological programs activated in mouse mammary epithelium during pregnancy.

Project description:The transcription factor STAT5 has long been recognized as an important mediator of prolactin induced mammary development during pregnancy. We have used mouse genetics and genome-wide analyses to determine how altering concentrations of STAT5A and STAT5B impacts different target promoters. Examination of genome-wide STAT5A, STAT5B, PolII and H3K4me3 in wild type (AABB) and Stat5a-null (BB) mammary tissues.

2012-09-18 | E-GEOD-40930 | biostudies-arrayexpress

Prolactin-inducible Stat5a-mediated and Stat5b-mediated gene profiles

Project description:Stat5a and Stat5b proteins are highly homologous with greater than 90% amino acid identity and share binding to the palindromic Stat5 consensus sequence, TTCNNNGAA, but individual roles of each transcription factor in breast cancer have not been thoroughly evaluated. To determine the degree of similarity between transcripts modulated by Stat5a and Stat5b proteins in human breast cancer, we utilized genome-wide transcript profiling to identify genes regulated specifically by Stat5a or Stat5b in response to prolactin.

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