Despite newer treatment modalities, overall mortality from AML still exceeds 50 percent. Differentiation agents have shown promise but due to lack of efficacy and toxicity we are still looking for additional or better agents. In the initial studies, G-CSF could override the differentiation block in leukemic cell lines and in some fresh AML cells. However, most responsive AML cells proliferated without differentiation upon exposure to G-CSF. Based on our recent studies we postulate that in AML cells, Stat3alpha activation may interfere with the G-CSF-driven differentiation signal. In this proposal, we plan to determine 1) if Stat3 is required for G-CSF-driven myeloid differentiation, and 2) the effect of altered relative levels of Stat3 isoforms Stat3alpha and Stat3beta on G-CSF-driven myeloid differentiation. By meals of antisense inhibition of Stat3 and use of a dominant negative of Stat3, we shall confirm the role of Stat3 in myelopoiesis. Then by overexpressing Stat3alpha, we shall examine the role of relative Stat3 isoforms level in G-CSF-driven myelopoiesis. The long-term goal of this project is to apply information gained from these studies to the design of new differentiation-inducing agents for the treatment of AML. Such therapies might target Stat3alpha at the level of its activation or expression in AML cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32CA077928-02
Application #
6077888
Study Section
Special Emphasis Panel (ZRG4-HEM-2 (01))
Program Officer
Lohrey, Nancy
Project Start
1999-10-01
Project End
Budget Start
1999-08-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030