Condorelli G L, Facchiano F, Valtieri M, Proietti E, Vitelli L, Lulli V, Huebner K, Peschle C, Croce C M
Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Cancer Res. 1996 Nov 15;56(22):5113-9.
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.
TAL-1基因编码一种碱性结构域-螺旋-环-螺旋蛋白，该蛋白参与正常造血的调控。在人类病理学中，TAL-1基因产物在小儿年龄段的高比例T细胞急性淋巴细胞白血病中表达；然而，其表达是否在肿瘤发生中具有因果作用尚未确定。在本报告中，我们描述了通过使用LCK启动子在淋巴组织中诱导tal-1蛋白表达而获得的小鼠转基因品系的表型。与对照小鼠相比，tal-1转基因动物的存活率要低得多。组织病理学分析显示为T细胞型淋巴瘤，通常包含少量B细胞成分。一些小鼠表现出明显的脾淋巴细胞耗竭。原代淋巴细胞培养显示对外源生长刺激有部分独立性，并增加了对低血清凋亡的抗性。为了进一步阐明tal-1的致癌潜力，将一株tal-1转基因小鼠与p53基因敲除小鼠杂交；与tal-1小鼠相比，这些动物的存活率降低了一半以上，组织病理学分析显示仅有T细胞淋巴瘤。这些数据表明，在T细胞中表达的TAL-1本身是一种强效癌基因，可能在大多数T细胞急性淋巴细胞白血病中发挥关键的白血病发生作用。
