Role of Tcl-1 in Lymphoid Development

在白血病中，非随机染色体易位已被确定为易患或引起细胞生长和/或存活的变化，从而促进恶性肿瘤。对人类致癌基因及其蛋白质结构机制的详细研究需要识别或开发动物模型以研究蛋白质功能。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倒位/易位的T细胞慢性淋巴细胞白血病（T-CLL）。染色体断裂点基因TcII和相关的MTCP 1基因最近已被克隆和表征，并且已经克隆了导致其潜在疾病的基因（ATM），并在小鼠中产生了无效突变（Atm-/-）。我们假设TcII在癌症的发展中起关键作用。此外，使用新分离的鼠TcII基因开发淋巴细胞增殖的小鼠模型将提供研究TcII蛋白及其在诱导导致CLL的成熟T细胞淋巴细胞增殖中的作用的理想机会。因此，我们提出了三个实验目的：1.检测TcII在小鼠胚胎发育过程中的表达。TcII的空间表达对于无效突变体分析和功能研究将是至关重要的。2 Tc 11转基因和Tc 11-/-缺失突变小鼠的建立和分析。这些菌株将是人类疾病动物模型的全面发展所必需的。3建立了哺乳动物T淋巴细胞增殖和慢性淋巴细胞白血病模型。Tcll -/-突变小鼠将与其他小鼠品系（例如Atm +/-小鼠）一起繁殖以重现人CLL。我们希望通过这些分子工具的开发，包括小鼠CLL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.