T-cell translocation gene 1 (Ttg-1), also called rhombotin, is deregulated upon translocation into the α/δ T-cell receptor loci in acute lymphoblastic leukemias bearing the t (11; 14)(p15; q11). Ttg-1 encodes a nuclear protein, expressed predominantly in neuronal cells, which belongs to a novel family of transcription factors possessing LIM domains. We utilized the lck proximal promoter to overexpress this candidate oncogene in immature thymocytes of transgenic mice. lck pr Ttg-1 mice develop immature, aggressive T-cell leukemia/lymphomas. Tumor incidence is proportional to the level of Ttg-1 expression. Most tumors contain CD4+ 8+ cells as well as CD4− 8+ cells, which have an immature rather than a mature peripheral phenotype. Ttg-1-induced tumorigenesis preferentially affects a minority population of thymocytes representing an immature CD4− 8+ intermediate stage between double-negative CD4− 8− cells and double-positive CD4+ 8+ cells. This model indicates that the aberrant expression of putative transcription factors plays a primary role in the genesis of T-cell acute lymphoblastic leukemias.