T-CELL-DIRECTED TAL-1 EXPRESSION INDUCES T-CELL MALIGNANCIES IN TRANSGENIC MICE

The TAL-1 gene specifies for a basic domain-helix-loop-helix protein, which is involved in the control of normal hematopoiesis. In human pat hology, the TAL-1 gene product is expressed in a high percentage of T- cell acute lymphoblastic leukemias in the pediatric age range; however , it has not been established whether the expression has a causal role in oncogenesis. In this report, we describe the phenotype of mouse tr ansgenic lines obtained by inducing tal-1 protein expression in lympho id tissues using the LCK promoter. The survival rate of tal-1 transgen ic animals was much lower as compared with control mice. Histopatholog ical analysis revealed lymphomas of T-cell type, often comprising a mi nor B-cell component. Some mice showed marked splenic lymphocyte deple tion. Primary lymphocyte cultures showed partial independence from exo genous growth stimuli and increased resistance to low-serum apoptosis. To further unravel the tal-1 oncogenic potential, a strain of tal-1 t ransgenic mice was crossbred with p53(-/-) mice; the survival rate in these animals was reduced by more than one-half when compared with tha t of tal-1 mice, and histopathological analysis revealed exclusively T -cell lymphomas. These data indicate that TAL-1, expressed in T cells, is per se a potent oncogene, which may exert a key leukemogenetic rol e in the majority of T-cell acute lymphoblastic leukemias.