Role of Tcl-1 in Lymphoid Development

在白血病中，非随机染色体易位已被确定易患或引起细胞生长和/或生存的改变，从而促进恶性肿瘤。人类致癌基因及其蛋白质结构机制的详细研究需要鉴定或开发动物模型，以便研究蛋白质功能。患有共济失调毛细血管扩张症（AT）的患者经常患有携带14q32.1-q11倒置/易位的T细胞慢性淋巴细胞白血病（T- cll）。染色体断点基因Tcll和相关的MTCP1基因最近被克隆和表征，负责它们的潜在疾病（ATM）的基因已被克隆，并在小鼠中产生零突变（ATM -/-）。我们假设Tcll在癌症的发展中起着关键作用。进一步使用新分离的小鼠Tcll基因建立小鼠淋巴细胞增殖模型，将为研究Tcll蛋白及其在诱导成熟T细胞淋巴细胞增殖导致CLL的作用提供理想的机会。因此，我们提出了三个实验目的：1 .评估Tcll在小鼠胚胎发育过程中的表达。Tcll的空间表达对于零突变分析和功能研究至关重要。2 .培养和分析Tcll转基因和Tcll -/- null突变小鼠。这些菌株对于人类疾病的动物模型的全面开发是必需的。3建立T细胞淋巴细胞增殖与CLL的哺乳动物模型。Tcll -/-突变小鼠将与其他小鼠株（如Atm +/-小鼠）繁殖，以重现人类CLL。我们期望通过这些分子工具的发展，包括CLL的小鼠模型，可以开发和测试人类疾病的治疗方法。

In leukemias, non-random chromosomal translocations have been determined to predispose or cause changes in cell growth and/or survival that promote malignancy. The detailed study of the mechanisms of human cancer causing genes and their protein structure requires the identification or development of animal models to allow the study of protein function. Patients with the disease ataxia telangiectasia (AT) frequently suffer from T cell chromic lymphocytic leukemia (T-CLL) carrying a 14q32.1-q11 inversion/translocation. The chromosomal breakpoint gene Tcll and the related MTCP1 genes have been recently cloned and characterized and the gene responsible for their underlying disease (ATM) has been cloned and a null mutation produced in mice (Atm-/-). We hypothesize that Tcll plays a critical role in the development of cancer. Further the use of the newly isolated murine Tcll gene for the development of a mouse model of lymphoproliferation will provide an ideal opportunity to study the Tcll protein and its role in inducing mature T cell lymphoproliferations that lead to CLL. Consequently, we propose three experimental aims: 1 Evaluate the expression of Tcll during murine embyrogenesis. The spatial expression of Tcll will be critical for null mutant analysis and functional studies. 2 Develop and analyze Tcll transgenic and Tcll -/- null mutant mice. These strains will be required for the full development of an animal model of human disease. 3 Establish a mammalian model of T cell lymphoproliferation and CLL. Tcll -/- mutant mice will be bred with other mouse strains, such as the Atm +/- mice to recapitulate human CLL. We expect that through the development of these molecular tools, including a murine model of CLL, therapies for the human disease can be developed and tested.