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Structurally Distinct Ligand-Binding or Ligand-Independent Notch1 Mutants Are Leukemogenic but Affect Thymocyte Development, Apoptosis, and Metastasis Differently¹

Elena Priceputu^2,*, Isabelle Bouallaga^2,*, YaoPing Zhang^2,*, Xiujie Li^*, Pavel Chrobak^*, Zaher S. Hanna^*,, Johanne Poudrier^*, Denis G. Kay^* and Paul Jolicoeur^3,*,,

^* Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montréal, Québec, Canada; Department of Microbiology and Immunology, Université de Montréal, Montréal, Québec, Canada; and Department of Experimental Medicine, McGill University, Montréal, Québec, Canada

We previously found that provirus insertion in T cell tumors of mouse mammary tumor virus/c-myc transgenic (Tg) mice induced two forms of Notch1 mutations. Type I mutations generated two truncated molecules, one intracellular (IC) (Notch1^IC) and one extracellular (Notch1^EC), while in type II mutations Notch1 was deleted of its C terminus (Notch1^CT). We expressed these mutants in Tg mice using the CD4 promoter. Both Notch1^IC and Notch1^CT, but not Notch1^EC, Tg mice developed double-positive (DP) thymomas. These disseminated more frequently in Notch1^CT Tg mice. Double (Notch1^IC x myc) or (Notch1^CT x myc) Tg mice developed thymoma with a much shorter latency than single Tg mice, providing genetic evidence of a collaboration between these two oncogenes. FACS analysis of preleukemic thymocytes did not reveal major T cell differentiation anomalies, except for a higher number of DP cells and an accumulation of TCR^highCD2^highCD25^high DP cells in Notch1^IC, and less so in Notch1^CT Tg mice. This was associated with enhanced in vivo thymocyte proliferation. However, Notch1^IC, but not Notch1^CT, DP thymocytes were protected against apoptosis induced in vivo by dexamethasone and anti-CD3 and in vitro by anti-CD3/CD28 Abs. This indicates that the C terminus of Notch1 and/or the conserved regulation by its ligands have a significant impact on the induced T cell phenotype. Therefore, Notch1^IC and Notch1^CT behave as oncogenes for T cells. Because these two Notch1 mutations are very similar to those described in some forms of human T cell leukemia, these Tg mice may represent relevant models of these human leukemias.

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