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T-Cell-directed TAL-1 Expression Induces T-Cell Malignancies in Transgenic Mice¹

Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [G. L. C., F. F., K. H., C. P., C. M. C.], and Department of Hematology-Oncology [M. V., L. V., V. L., C. P.] and Department of Virology [E. P.], Istituto Superiore di Sanità, 00161 Rome, Italy

The TAL-1 gene specifies for a basic domain-helix-loop-helix protein, which is involved in the control of normal hematopoiesis. In human pathology, 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 transgenic lines obtained by inducing tal-1 protein expression in lymphoid tissues using the LCK promoter.

The survival rate of tal-1 transgenic animals was much lower as compared with control mice. Histopathological analysis revealed lymphomas of T-cell type, often comprising a minor B-cell component. Some mice showed marked splenic lymphocyte depletion. Primary lymphocyte cultures showed partial independence from exogenous growth stimuli and increased resistance to low-serum apoptosis. To further unravel the tal-1 oncogenic potential, a strain of tal-1 transgenic mice was crossbred with p53^-/- mice; the survival rate in these animals was reduced by more than one-half when compared with that 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 role in the majority of T-cell acute lymphoblastic leukemias.

¹ This work was supported in part by National Cancer Institute Outstanding Investigator Grant CA39860 (to C. M. C.) and Grant CA21124 (to K. H.). G. L. C. is the recipient of an AIDS fellowship from the Ministry of Health, Rome, Italy.

² Both authors contributed equally to this work.

³ Present address: Istituto Dermopatico dell'Immacolata, Lab. of Vascular Pathology, Via Monti di Creta 104, 00167 Rome, Italy.

⁴ To whom requests for reprints should be addressed, at Kimmel Cancer Center, Jefferson Medical College, 233 South 10th Street, BLSB, Room 1050, Philadelphia, PA 19107-5799.

Received 9/11/96. Accepted 10/ 4/96.

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