Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice

Diana Bellavia, Antonio F. Campese, Edoardo Alesse, Alessandra Vacca, Maria Pia Felli, Anna Balestri, Antonella Stoppacciaro, Cecilia Tiveron, Laura Tatangelo, Mirella Giovarelli, Carlo Gaetano, Luigi Ruco, Eric S. Hoffman, Adrian C. Hayday, Urban Lendahl, Luigi Frati, Alberto Gulino, Isabella Screpanti

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3337-3348
Number of pages12
JournalEMBO Journal
Volume19
Issue number13
Publication statusPublished - Jul 3 2000

Keywords

  • NF-κB
  • Notch3
  • Pre-TCR
  • T-cell malignancy

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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  • Cite this

    Bellavia, D., Campese, A. F., Alesse, E., Vacca, A., Felli, M. P., Balestri, A., Stoppacciaro, A., Tiveron, C., Tatangelo, L., Giovarelli, M., Gaetano, C., Ruco, L., Hoffman, E. S., Hayday, A. C., Lendahl, U., Frati, L., Gulino, A., & Screpanti, I. (2000). Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO Journal, 19(13), 3337-3348.