The molecular role of lkaros in leukemogenesis

肿瘤抑制基因是一组基因，其功能经常通过突变而丧失 癌细胞我们已经将Ikaros鉴定为具有新型T谱系特异性肿瘤特征的蛋白质 抑制器。在100%的转化率下，小鼠中缺乏Ikaros活性导致白血病发生。我们有 显示了使用新细胞培养系统，Ikaros基因恢复为Ikaros无效T白血病细胞 系导致细胞周期停滞和启动T细胞特异性基因表达程序。我们还 确定细胞周期调节因子p27 kip 1作为转录激活的潜在遗传靶点， 伊卡洛斯有趣的是，p27 kip 1基因表达水平的降低与肿瘤的发生机制有关。 Bcr/Abl诱导人白血病，提示Ikaros无效T细胞中p27 kip 1水平降低可能维持 这是它们非凡的变形倾向的关键Ikaros可能在人类细胞中发挥肿瘤抑制作用 此外，由于分析的婴儿和儿童急性淋巴细胞白血病的高百分比显示， Ikaros基因表达的缺陷。本提案中描述的实验的目标是定义 缺乏Ikaros活性导致白血病发生的机制。我们将通过以下方式做到这一点：1）识别 Ikaros的功能/相互作用域对其在生长控制中的作用至关重要，2）通过以下方式定义机制： 其中Ikaros控制p27 kip 1基因的表达，以及3）鉴定Ikaros的功能/相互作用结构域 这是其在启动T细胞特异性基因表达程序中所必需的。这些研究还将包括 分析Ikaros与Brg-1和Swi/Snf染色质重塑复合物在T细胞中的作用， 细胞生长控制和诱导T细胞特异性基因表达程序。难以确定 Ikaros功能的机制是由于，至少部分是由于缺乏一个容易操纵的实验 系统然而，我们独特的细胞培养系统由Ikaros null T白血病细胞系组成， 使用逆转录病毒转导进行遗传改变是定义Ikaros功能机制的有效工具。这 系统，结合Ikaros无效小鼠，使我们唯一有资格定义的机械作用， 这个新的肿瘤抑制基因

Tumor suppressor genes are a group of genes whose function is frequently lost through mutation cancer cells. We have identified Ikaros as a protein with characteristics of a novel T lineage specific tumor suppressor. With 100% penetrance, lack of Ikaros activity in mice results in leukemogenesis. We have shown, using a novel cell culture system, that genetic restoration of Ikaros to an Ikaros null T leukemia cell line results in cell cycle arrest and initiation of a T cell specific program of gene expression. We have also identified the cell cycle regulator, p27kip1, as a potential genetic target for transcriptional activation by Ikaros. Interestingly, decreased levels of p27kip1 gene expression have been linked to the mechanism of Bcr/Abl induced human leukemia, suggesting that decreased p27kip1 levels in Ikaros null T cells may hold the key to their remarkable propensity to transform. Ikaros may play a tumor suppressive role in human cells as well, since a high percentage of analyzed infant and childhood acute lymphocytic leukemias display defects in Ikaros gene expression. The goal of the experiments described in this proposal is to define mechanisms by which lack of Ikaros activity leads to leukemogenesis. We will do this by: 1) identifying Ikaros' functional/interaction domains essential to its role in growth control, 2) defining the mechanism by which Ikaros controls expression of the p27kip1 gene and 3) identifying Ikaros' functional/interaction domains required for its role in initiating a T cell specific program of gene expression. These studies will also include analyses of the role of Ikaros' association with Brg-1 and the Swi/Snf chromatin remodeling complexes in T cell growth control and induction of a T cell specific program of gene expression. The difficulty in defining mechanisms of Ikaros function has been due, at least in part, to lack of an easily manipulated experimental system. However, our unique cell culture system consisting of an Ikaros null T leukemia cell line that can be genetically altered using retroviral transduction is a potent tool to define mechanisms of Ikaros function. This system, in conjunction with the Ikaros null mice, makes us uniquely qualified to define the mechanistic role of this novel tumor suppressor gene.