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。要详细研究人类致癌基因及其蛋白质结构的机制，需要识别或发展动物模型，以便研究蛋白质的功能。共济失调毛细血管扩张症(AT)患者常患有携带14q32.1-q11倒位/易位的T细胞慢性淋巴细胞白血病(T-CLL)。最近，染色体断裂点基因Tcl1和相关的MTCP1基因被克隆和鉴定，并克隆了导致其潜在疾病的基因(ATM)，并在小鼠中产生了零突变(ATM-/-)。我们假设Tcl1在癌症的发生发展中起关键作用。此外，利用新分离的小鼠Tcl1基因建立小鼠淋巴增殖模型，将为研究Tcl1蛋白及其在诱导成熟T细胞淋巴增殖导致CLL中的作用提供理想的机会。因此，我们提出了三个实验目标：1评价Tcl1在小鼠胚胎发育过程中的表达。Tcl1的空间表达将是零突变分析和功能研究的关键。2建立和分析Tcl1转基因和Tcl1/缺失突变小鼠。这些毒株将是全面发展人类疾病动物模型所必需的。3建立T细胞增殖和CLL的哺乳动物模型。Tcll-/-突变小鼠将与其他品系的小鼠一起培育，如ATM+/-小鼠，以重现人类CLL。我们希望通过开发这些分子工具，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.