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 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.
Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
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Condorelli
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Facchiano
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Valtieri
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Proietti
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Vitelli
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Lulli
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Huebner
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Peschle
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D017502:Adenovirus E2 Proteins / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D017252:CD3 Complex / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D017502:Adenovirus E2 Proteins; D051792:Basic Helix-Loop-Helix Proteins; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human