Submitted April 11, 2007
Accepted September 16, 2007
A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling
Katherine Bessette, Mark Lang, Roy A. Fava, Martin Grundy, Jennifer Heinen, Laurie Horne, Rosanne Spolski, Amin Al-Shami, Herbert C. Morse III, Warren J Leonard, and John A Kelly*
White River Junction VA, White River Junction, VT, United States
Department of Micro/Immunology, Dartmouth Medical School, Lebanon, NH, United States
Department of Medicine, Dartmouth Medical School, Lebanon, NH, United States
Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, Bethesda, MD, United States
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, Rockville, MD, United States
* Corresponding author; email: john.a.kelly{at}dartmouth.edu.
Stat5 proteins are critical signaling molecules activated by many cytokines. Within the immune system, Stat5 plays important roles related to the development of thymocytes and proliferation of T-cells. Stat5 has been implicated in malignant transformation, and moreover, the activated tyrosine phosphorylated form of Stat5 is frequently observed in human lymphomas. We previously demonstrated the oncogenic potential of Stat5, with thymic lymphoblastic lymphomas developing in a significant proportion of transgenic (TG) mice over-expressing Stat5a or Stat5b in lymphocytes. In addition, immunization or expression of a T-cell receptor (TCR) transgene augmented the rate of tumor formation. Here we investigate the mechanism of Stat5-mediated lymphomagenesis by exploring the contributions of MHC/TCR and pre-TCR signals. We present data demonstrating that Stat5b TG mice unexpectedly develop CD8+ lymphoma even in the absence of either pre-TCR signaling and normal thymic selection. Indeed, acceleration of Stat5b TG-mediated lymphoma occurred on TCR
-/- and pre-TCR-/- backgrounds. In light of these data, we propose a model in which alterations in T-cell development at the DN/DP stages cooperate with cytokine-mediated pathways in immature thymocytes to give rise to lymphoblastic T-cell lymphomas in Stat5b TG mice.
