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

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(+) transi tion, controlled by pre-T-cell receptor signaling, To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expres sing lck promoter-driven intracellular Notch3, Thymuses of young transgenic s showed an increased number of thymocytes, particularly late CD4(-)8(-) ce lls, a failure to down-regulate CD25 in post-CD4(-)8(-) subsets and sustain ed activity of NF-kappa B, Subsequently, aggressive multicentric T-cell lym phomas developed with high penetrance, Tumors sustained characteristics of immature thymocytes, including expression of CD25, pT alpha and activated N F-kappa B via IKR alpha-dependent degradation of I kappa B alpha and enhanc ement of NF-kappa B-dependent anti-apoptotic and proliferative pathways. To gether, these data identify activated Notch3 as a link between signals lead ing to NF-kappa B activation and T-cell tumorigenesis. The phenotypes of pr e-malignant thymocytes and of lymphomas indicate a novel and particular rol e for Notch3 in co-ordinating growth and differentiation of thymocytes, acr oss the pre-T/T cell transition, consistent with the normal expression patt ern of Notch3.