"These findings provide a strong rationale for the use and development of drugs that target the components of this network rather than focusing on the activity of KIT alone."
Marcucci, Garzon, first author Shujun Liu, assistant professor of internal medicine, and their colleagues began this study by showing that patients with mutations in the KIT gene in their leukemic cells had the highest levels of the KIT protein in those cells, and that these patients also had the poorest survival.
"This told us that the amount of the protein in cancer cells is important to the disease process," Liu says.
Using laboratory-grown AML cells, the researchers identified the series of molecules that control the amount of KIT protein, showing for the first time that a microRNA called miR-29b, along with several well-known cancer-related genes, regulate KIT production.
Normally, these elements work in a balanced fashion to produce the correct amount of KIT protein for healthy cell survival and proliferation. That normal balance is derailed when gene mutations or other genetic damage occurs in the network and promotes the overproduction of the KIT protein.
"It becomes a vicious circle because no matter where genetic damage occurs, the result is the same overactivation of the circle, overexpression of the KIT protein, and proliferation of leukemic cells," Liu says.
Using a mouse model, the researchers showed that raising the amount of mutated KIT protein causes leukemia, and drugs that target the network lower the amount of that protein and drive the leukemia into remission. These drugs included proteasome inhibitors, histone deacetylase inhibitors, along with inhibitors of molecules called NFĸB and Sp1.
|Contact: Darrell E. Ward|
Ohio State University Medical Center