The ETS family of transcription factors has been implicated in the development of leukemias, lymphomas and sarcomas. We have previously identified a member of this family, FLI1, whose retroviral activation results in the development of hematological tumors. The FLI1 gene is oncogenically activated in the transformed cells of patients with Ewing's sarcoma by the t(11;22) translocation. The long range goal of this research is to understand the function of FLI1 in the regulation of cellular differentiation and development and how dysregulated FLI1 can lead to the development of disease. Our preliminary data indicate that FLI1 expression can promote differentiation of leukemic cells towards the megakaryocytic lineage. In addition, we have generated targeted cell lines that carry a mutant allele for the Fli1 gene. We propose to use these in vitro and in vivo systems to examine the consequences of over- and under-expression of FLI1. Ultimately, this will help us identify relevant target genes controlled by this member of the ETS gene family. We hypothesize that FLI1 functionally regulates genes that are critical for cellular differentiation, specifically genes encoding cell-specific proteins and genes that encode proteins that control cellular proliferation.
The specific aims of this project are to: (1) define the role of FLI1 in the differentiation of human erythroleukemia cells (K562) by deletion analysis of FLI1; identify the domains required for its biological effects; to determine if ERG can functionally substitute for FLI1; (2) identify FLI1 target genes associated with promotion of cellular differentiation and regulation of cell growth by analysis of gene expression in an inducible system; and (3) to define the role of FLi1 in development by disruption of Fli1 gene in ES cells and in mice by homologous recombination; characterize the pathology of the mutant mice; including hematopoietic cell lineage profile analysis. The experiments proposed will provide important understanding into the mechanisms that control lineage selection during hematopoiesis and cellular proliferation, and insights into oncogenesis caused by the disruption of these controls.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078582-03
Application #
6340782
Study Section
Project Start
2000-08-01
Project End
2001-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$154,069
Indirect Cost
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Duchi, Serena; Fagnocchi, Luca; Cavaliere, Valeria et al. (2010) Drosophila VHL tumor-suppressor gene regulates epithelial morphogenesis by promoting microtubule and aPKC stability. Development 137:1493-503
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Moussa, Omar; LaRue, Amanda C; Abangan Jr, Romeo S et al. (2010) Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1. Mol Cell Biol 30:5194-206
Elkareh, Jihad; Periyasamy, Sankaridrug M; Shidyak, Amjad et al. (2009) Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: implications for uremic cardiomyopathy. Am J Physiol Renal Physiol 296:F1219-26
Shirai, Keisuke; Sera, Yasuhiko; Bulkeley, William et al. (2009) Hematopoietic stem cell origin of human fibroblasts: cell culture studies of female recipients of gender-mismatched stem cell transplantation and patients with chronic myelogenous leukemia. Exp Hematol 37:1464-71

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