Premium
Constitutive activation of NF‐κB and T‐cell leukemia/lymphoma in Notch3 transgenic mice
Author(s) -
Bellavia Diana,
Campese Antonio F.,
Alesse Edoardo,
Vacca Alessandra,
Felli Maria Pia,
Balestri Anna,
Stoppacciaro Antonella,
Tiveron Cecilia,
Tatangelo Laura,
Giovarelli Mirella,
Gaetano Carlo,
Ruco Luigi,
Hoffman Eric S.,
Hayday Adrian C.,
Lendahl Urban,
Frati Luigi,
Gulino Alberto,
Screpanti Isabella
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.13.3337
Subject(s) - biology , lymphoma , leukemia , transgene , cancer research , genetically modified mouse , bcl10 , nfkb1 , microbiology and biotechnology , immunology , genetics , gene , transcription factor
The multiplicity of Notch receptors raises the question of the contribution of specific isoforms to T‐cell development. Notch3 is expressed in CD4 − 8 − thymocytes and is down‐regulated across the CD4 − 8 − to CD4 + 8 + transition, controlled by pre‐T‐cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter‐driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4 − 8 − cells, a failure to down‐regulate CD25 in post‐CD4 − 8 − subsets and sustained activity of NF‐κB. Subsequently, aggressive multicentric T‐cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTα and activated NF‐κB via IKKα‐dependent degradation of IκBα and enhancement of NF‐κB‐dependent anti‐apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF‐κB activation and T‐cell tumorigenesis. The phenotypes of pre‐malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in co‐ordinating growth and differentiation of thymocytes, across the pre‐T/T cell transition, consistent with the normal expression pattern of Notch3.