A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling.
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 overexpressing 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 major histocompatibility complex (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 or normal thymic selection. Indeed, acceleration of Stat5b transgene-mediated lymphoma occurred on TCRalpha(-/-) and pre-TCRalpha(-/-) backgrounds. In light of these data, we propose a model in which alterations in T-cell development at the double-negative/double-positive (DN/DP) stages cooperate with cytokine-mediated pathways in immature thymocytes to give rise to lymphoblastic T-cell lymphomas in Stat5b TG mice.
Bessette
Katherine
K
White River Junction Veteran's Association, White River Junction, VT, USA.
Lang
Mark L
ML
Fava
Roy A
RA
Grundy
Martin
M
Heinen
Jennifer
J
Horne
Laurie
L
Spolski
Rosanne
R
Al-Shami
Amin
A
Morse
Herbert C
HC
Leonard
Warren J
WJ
Kelly
John A
JA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology; D008285:Major Histocompatibility Complex / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D019076:Transgenes / Q000502:physiology
D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse