Lai, Wi (NIEHS)
Blackshear, Perry (NIEHS)
The disclosed invention provides materials and methods to treat granulocytopenia (low white cell count in the blood) which is characterized by a reduced number of granulocytes (relative) or an absence of granulocytes (absolute). This condition is commonly associated with cancer chemotherapy, but is seen less frequently in a number of conditions including the use of propylthiouracil, radiotherapy for marrow ablation for bone marrow transplantation, aplastic anemia, systemic lupus erythematosus, AIDS and a variety of other situations. The invention proposes a method to increase GM-CSF levels in a treated subject, and this increase is achieved by inhibiting the degradation of GM-CSF messenger RNA (mRNA). Tristetraprolin (TTP) is one member of a family of cys-cys-cys-his (CCCH) zinc finger proteins, and it is a factor that binds to and causes the instability of GM-CSF mRNA. Methods are provided for the development of screening assays for molecules that inhibit the binding of TTP and its related proteins to GM-CSF mRNA, or otherwise inhibit the effect of TTP to promote breakdown of the mRNA, leading in turn to increased mRNA stability and enhanced production of GM-CSF. Compounds identified by such screens, and their derivatives, could be useful in treating granulocytopenia from whatever cause.