Enhanced T Cell Lymphoma in NOD.Stat5b Transgenic Mice Is Caused by Hyperactivation of Stat5b in CD8 Thymocytes

Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2013; 8(2):e56600. DOI: 10.1371/journal.pone.0056600
Source: PubMed


Activation of signal transducers and activators of transcription (STAT) proteins may be critical to their oncogenic functions as demonstrated by the development of B-cell lymphoma/leukemia in transgenic (TG) mice overexpressing a constitutively activated form of Stat5b. However, low incidence of CD8 T cell lymphoma was observed in B6 transgenic mice overexpressing a wild-type Stat5b (B6.Stat5b) despite of undetectable Stat5b phosphorylation and the rate of lymphomagenesis was markedly enhanced by immunization or the introduction of TCR transgenes [1]. Here, we report that the wild-type Stat5b transgene leads to the acceleration and high incidence (74%) of CD8 T cell lymphoblastic lymphomas in the non-obese-diabetic (NOD) background. In contrast to the B6.Stat5b mice, Stat5b in transgenic NOD (NOD.Stat5b) mice is selectively and progressively phosphorylated in CD8 thymocytes. Stat5 phosphorylation also leads to up-regulation of many genes putatively relevant to tumorigenesis. Treatment of NOD.Stat5b mice with cancer chemopreventive agents Apigenin and Xanthohumol efficiently blocked lymphomagenesis through reduction of Stat5 phosphorylation and genes up-regulated in the NOD.Stat5b mice. These results suggest that NOD genetic background is critical to the Stat5b-mediated lymphomagenesis through regulation of Stat5 hyperactivation. NOD.Stat5b mouse is an excellent model for studying the molecular mechanisms underlying lymphomagenesis and testing novel chemoprevention strategies.

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Available from: Ashok Sharma, Oct 07, 2015
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    ABSTRACT: Background Contact Hypersensitivity Assay (CHS) faithfully models human allergies. The Stat5 transcription factors are essential both for lymphocytes development and acute immune responses. Although consequences of Stat5 ablation and transgenic over expression for the lymphocytes development and functions have been extensively studied, the role of Stat5 gene dosage in contact allergies have not been addressed.Objective We investigated effect of Stat5 gene dosage modulation in contact allergies using CHS in mice.Methods Transgenic animals heterozygous for the germline Stat5 null allele were subjected to CHS assay. To dissect cell type sensitive to Stat5 gene dosage, animals with Stat5 haplo-insufficiency in T cells, where one Stat5 allele was removed by Lck-Cre- mediated deletion (Stat5ΔT/+), were tested by CHS assay. Frequency of T -, B- cells and monocytes were analyzed in Stat5ΔT/+ and wild type animals by flow cytometry. Proliferation of Stat5ΔT/+ CD8+ T cells were studied in vitro by stimulation with IL-4 and IL-2 cytokines and changes in expression of Stat5 target genes were assayed by quantitative real time PCR assay.ResultHaplo-insufficiency of Stat5 in T cells leads to reduction of CD8+ T cells in all lymphoid organs and attenuates CHS response. Stat5ΔT/+ CD8+ T cells failed to fully activate Stat5 dependent expression of cell cycle/survival target genes, such as bcl-2 and pim1, and to proliferate efficiently in response to IL-2 and IL-4 cytokine.Conclusion: Our data identify Stat5 as a dose dependent regulator of CD8+ T cell functions in contact allergies and suggest that modulation of Stat5 dosage could be used to target contact allergies in humans.This article is protected by copyright. All rights reserved.
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