Kelliher M A, Seldin D C, Leder P
Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USA.
EMBO J. 1996 Oct 1;15(19):5160-6.
Ectopic activation of the TAL-1 gene in T lymphocytes occurs in the majority of cases of human T cell acute lymphoblastic leukemia (T-ALL), yet experiments to date have failed to demonstrate a direct transforming capability for tal-1. The tal-1 gene product is a serine phosphoprotein and basic helix-loop-helix (bHLH) transcription factor known to regulate embryonic hematopoiesis. We have established a transgenic mouse model in which tal-1 mis-expression in the thymus results in the development of clonal T cell lymphoblastic leukemia/lymphoma. Thus, overexpression of tal-1 alone can be transforming, verifying its pathogenic role in human T-ALL. In addition, leukemogenesis is accelerated dramatically by transgenic co-expression of tal-1 and the catalytic subunit of casein kinase IIalpha (CKIIalpha), a serine/threonine protein kinase known to modulate the activity of other bHLH transcription factors. Although tal-1 is a substrate for CKII, the synergy of the tal-1 and CKIIalpha transgenes appears to be indirect, perhaps mediated through the E protein heterodimeric partners of tal-1. These studies prove that dysregulated tal-1 is oncogenic, providing a direct molecular explanation for the malignancies associated with TAL-1 activation in human T-ALL.
T淋巴细胞中TAL-1基因的异位激活发生在大多数人类T细胞急性淋巴细胞白血病（T-ALL）病例中，但迄今为止的实验未能证明tal-1具有直接的转化能力。tal-1基因产物是一种丝氨酸磷酸蛋白和碱性螺旋-环-螺旋（bHLH）转录因子，已知其可调节胚胎造血。我们建立了一种转基因小鼠模型，其中胸腺中tal-1的错误表达导致克隆性T细胞淋巴细胞白血病/淋巴瘤的发生。因此，单独过表达tal-1就具有转化能力，证实了其在人类T-ALL中的致病作用。此外，通过tal-1与酪蛋白激酶IIα（CKIIα）催化亚基的转基因共表达，白血病发生显著加速，CKIIα是一种丝氨酸/苏氨酸蛋白激酶，已知其可调节其他bHLH转录因子的活性。尽管tal-1是CKII的底物，但tal-1和CKIIα转基因的协同作用似乎是间接的，可能是通过tal-1的E蛋白异二聚体伴侣介导的。这些研究证明失调的tal-1具有致癌性，为人类T-ALL中与TAL-1激活相关的恶性肿瘤提供了直接的分子解释。
