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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104962-02
Application #
7214618
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2006-04-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$203,388
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611