The molecular role of lkaros in leukemogenesis

肿瘤抑制基因是一组功能经常因突变而丧失的基因 癌细胞。我们已经确认Ikaros是一种具有新的T系特异性肿瘤特征的蛋白质 抑制者。在100%外显性的情况下，小鼠体内缺乏Ikaros活性会导致白血病发生。我们有 显示了使用一种新型细胞培养系统，将Ikaros基因恢复到Ikaros零T白血病细胞 LINE可导致细胞周期停滞并启动T细胞特异性基因表达程序。我们还有 将细胞周期调节因子p27kip1确定为转录激活的潜在遗传靶点 伊卡洛斯。有趣的是，p27kip1基因表达水平的降低与 Bcr/Abl诱发人类白血病，提示Ikaros零T细胞中p27kip1水平降低可能持续 它们非凡的变形倾向的关键。伊卡洛斯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性白血病的比例很高 伊卡洛斯基因表达缺陷。本提案中描述的实验的目标是定义 伊卡洛斯缺乏活性导致白血病发生的机制。我们将通过以下方式完成此任务：1)确定 Ikaros的功能/相互作用领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 哪个Ikaros控制p27kip1基因的表达以及3)确定Ikaros的功能/相互作用结构域 它在启动T细胞特异性基因表达程序中所需的作用。这些研究还将包括 Ikaros与Brg-1和Swi/SNF染色质重塑复合体在T细胞中的作用分析 控制细胞生长并诱导T细胞特异的基因表达程序。很难定义 伊卡洛斯的作用机制至少在一定程度上是由于缺乏易于操作的实验 系统。然而，我们独特的细胞培养系统由Ikaros空T白血病细胞系组成，可以 利用逆转录病毒转导进行基因改变是确定Ikaros功能机制的有效工具。这 系统，与Ikaros空鼠标相结合，使我们唯一有资格定义 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.