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