T-cell-directed TAL-1 expression induces T-cell malignancies in transgenic mice

• Published in: Cancer research (Chicago, Ill.) Vol. 56; no. 22; pp. 5113 - 5119
• Main Authors: CONDORELLI, G. L, FACCHIANO, F, VALTIERI, M, PROIETTI, E, VITELLI, L, LULLI, V, HUEBNER, K, PESCHLE, C, CROCE, C. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-11-1996
• Subjects: Adenovirus E2 Proteins - metabolism; Animal tumors. Experimental tumors; Animals; Basic Helix-Loop-Helix Transcription Factors; Biological and medical sciences; CD3 Complex - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Experimental malignant blood diseases; Gene Deletion; Genes, p53 - genetics; Humans; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - immunology; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - mortality; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oncogene Proteins, Fusion - metabolism; Oncogenes - genetics; Oncogenes - physiology; Phenotype; Proto-Oncogene Proteins; RNA, Messenger - metabolism; Spleen - metabolism; T-Cell Acute Lymphocytic Leukemia Protein 1; T-Lymphocytes - metabolism; Thymus Gland - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; Animal model; Pathogenesis; Acute; Rodentia; Transgenic animal; Malignant hemopathy; Carcinogenesis; Lymphoma; Vertebrata; Mammalia; Mouse; Lymphoproliferative syndrome; T-Lymphocyte; Acute lymphocytic leukemia; Onc gene
• ISSN: 0008-5472; 1538-7445

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.