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 (2014). Postnatal Notch1 activation induces T‑cell malignancy in conditional and inducible mouse models. International journal of oncology, 45(5), pp. 1997-2004. Spandidos Publications 10.3892/ijo.2014.2626

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Deutsch, Urban

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1019-6439

Publisher:

Spandidos Publications

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

07 Apr 2015 13:21

Last Modified:

07 Apr 2015 13:21

Publisher DOI:

10.3892/ijo.2014.2626

PubMed ID:

25175815

URI:

https://boris.unibe.ch/id/eprint/66369

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