EXCLUSIVE DEVELOPMENT OF T-CELL NEOPLASMS IN MICE TRANSPLANTED WITH BONE-MARROW EXPRESSING ACTIVATED NOTCH ALLELES

Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leuk emias/lymphomas containing a t(7;9) chromosomal translocation; however , its role in oncogenesis has been unclear. Using a bone marrow recons titution assay with cells containing retrovirally transduced TAN1 alle les, we analyzed the oncogenic potential of both nuclear and extranucl ear forms of truncated TAN1 in hematopoietic cells. Although the Molon ey leukemia virus long terminal repeat drives expression in most hemat opoietic cell types, retroviruses encoding either form of the TAN1 pro tein induced clonal leukemias of exclusively immature T cell phenotype s in similar to 50% of transplanted animals. Al tumors overexpressed t runcated TAN1 of the size and subcellular localization predicted from the structure of the gene. These results show that TAN1 is an oncoprot ein and suggest that truncation and overexpression are important deter minants of transforming activity. Moreover, the murine tumors caused b y TAN1 in the bone marrow transplant model are very similar to the TAN 1-associated human tumors and suggest that TAN1 may be specifically on cotropic for T cells.