The objective of the present study is to understand the normal hematopoiesis and malignant transformation of hematopoietic cells by studying biological functions of two genes, Ikaros and Helios. Ikaros encodes a zinc finger protein involved in heritable gene silencing. Gene disruption experiments have shown that expression of Ikaros is necessary for the development of both B and T cells and suggested that Ikaros can act as a tumor suppressor. Helios encodes a protein that is structurally similar to Ikaros and is only expressed in T cells. The biological function of Helios is unknown. ? ? The aims of this proposal are:
Research Aim #1 : Study the molecular mechanisms by which Ikaros affects cellular proliferation and differentiation. We will identify the constitutively phosphorylated amino acids in this protein. Phosphomimetic experiments will be performed to study how the phosphorylation status of particular amino acid(s) affects Ikaros function. We will study how overexpressing particular phosphomimetic Ikaros mutants affects cellular proliferation.
Research Aim #2 : Determine the functional significance of the phosphorylation of Ikaros protein at an evolutionarily conserved linker sequence. We will try to identify the kinase that phosphorylates this conserved linker and study the pathway involved.
Research Aim #3 : Determine the role of Helios in human malignancies. Our preliminary data suggest that expression of Helios in B cells contributes to malignant transformation in mouse and human. The molecular mechanism of how Helios promotes malignant transformation will be studied. We will establish the incidence and significance of Helios expression in human malignancies and determine the molecular mechanisms by which Helios affects B cell development in humans. These studies will provide important information on the mechanisms controlling development and proliferation of hematopoietic cells and will yield insights into the pathophysiology and treatment of leukemia. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K22)
Project #
1K22CA111392-01A1
Application #
6966801
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2005-08-12
Project End
2008-07-31
Budget Start
2005-08-12
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$162,540
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Parrish, Yasmin Khan; Baez, Ineavely; Milford, Terry-Ann et al. (2009) IL-7 Dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. J Immunol 182:4255-66
Popescu, Marcela; Gurel, Zafer; Ronni, Tapani et al. (2009) Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. J Biol Chem 284:13869-80
Gurel, Zafer; Ronni, Tapani; Ho, Sam et al. (2008) Recruitment of ikaros to pericentromeric heterochromatin is regulated by phosphorylation. J Biol Chem 283:8291-300
Ronni, Tapani; Payne, Kimberly J; Ho, Sam et al. (2007) Human Ikaros function in activated T cells is regulated by coordinated expression of its largest isoforms. J Biol Chem 282:2538-47