Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

Liu,Ju; Dong,Fengyun; Fung,Iris; Chen,Edwin; Allen,Thaddeus  D.; Deutsch,Urban; Lobe,Corrinne  G.

doi:10.3892/ijo.2014.2626

Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models

Authors:
- Ju Liu
- Fengyun Dong
- Iris Fung
- Edwin Chen
- Thaddeus D. Allen
- Urban Deutsch
- Corrinne G. Lobe
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Affiliations: Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China, Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, Toronto, ON M4N 3M5, Canada, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Molecular and Cellular Biology Division, Sunnybrook Health Science Centre, Toronto, ON M4N 3M5, Canada, Theodor‑Kocher‑Institute, University of Berne, 3012 Berne, Switzerland
Published online on: August 29, 2014 https://doi.org/10.3892/ijo.2014.2626
Pages: 1997-2004

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Abstract

The Notch1 signaling pathway is essential for hematopoietic development. However, the effects of postnatal activation of Notch1 signaling on hematopoietic system is not yet fully understood. We previously generated ZEG‑IC‑Notch1 transgenic mice that have a floxed β‑geo/stop signal between a CMV promoter and intracellular domain of Notch1 (IC‑Notch1). Constitutively active IC‑Notch1 is silent until the introduction of Cre recombinase. In this study, endothelial/hematopoietic specific expression of IC‑Notch1 in double transgenic ZEG‑IC‑Notch1/Tie2‑Cre embryos induced embryonic lethality at E9.5 with defects in vascular system but not in hematopoietic system. Inducible IC‑Notch1 expression in adult mice was achieved by using tetracycline regulated Cre system. The ZEG‑IC‑Notch1/Tie2‑tTA/tet‑O‑Cre triple transgenic mice survived embryonic development when maintained on tetracycline. Post‑natal withdrawal of tetracycline induced expression of IC‑Notch1 transgene in hematopoietic cells of adult mice. The triple transgenic mice displayed extensive T‑cell infiltration in multiple organs and T‑cell malignancy of lymph nodes. In addition, the protein levels of p53 and alternative reading frame (ARF) were decreased in lymphoma‑like neoplasms from the triple transgenic mice while their mRNA expression remained unchanged, suggesting that IC‑Notch1 might repress ARF‑p53 pathway by a post‑transcriptional mechanism. This study demonstrated that activation of constitutive Notch1 signaling after embryonic development alters adult hematopoiesis and induces T‑cell malignancy.

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