Production of blood cells in humans is controlled by a rare and specialized population of cells called stem cells, which reside mostly in the bone marrow. Stem cells are absolutely required to produce all of the many types of differentiated cells found in healthy blood. Therefore, diseases that affect stem cells are almost always serious and frequently life threatening. One form of stem cell disease is the blood cancer chronic myelogenous leukemia (CML). CML arises when a specific type of mutation occurs in the DNA of a normal stem cell. The damage created by this mutation causes profound changes in stem cell behavior. Most importantly, the CML stem cell produces large numbers of blood tumor cells known as blast cells, which rapidly outgrow normal cells and take over the blood system. Untreated, this condition is uniformly fatal.

In the past, therapies for CML have focused on the tumor blast cells because they are very abundant and clearly represent the most immediate problem for patients. While killing blast cells can provide short-term relief, if the CML stem cells are not also destroyed, the tumor will always re-grow and patients will relapse. The situation is analogous to pulling a weed, but failing to get the root. Since abnormal stem cells lie at the root of CML, it is critical that they be killed in order to provide durable cures for the disease. Unfortunately, standard drug regimens used in cancer treatment are not effective against CML stem cells.

In recent years a remarkable new drug, Gleevec, has been very successful in killing CML blast cells, providing remission for many patients. However, recent studies have shown that Gleevec does not kill CML stem cells, and consequently, patients remain at risk of relapse. Furthermore, patients with advanced forms of CML do not always respond to Gleevec. Therefore, developing treatments that specifically target CML stem cells is still a high priority for medical research.

In an effort to more effectively target leukemia stem cells, we recently developed a unique drug treatment strategy. This approach is based on the use of a family of drugs called proteasome inhibitors, which are agents that block protein degradation machinery in human cells. Our studies have demonstrated that proteasome inhibitors can effectively destroy stem cells in acute myelogenous leukemia (AML), a disease that is closely related to CML. Importantly, these studies also showed that proteasome inhibitors have almost no effect on normal stem cells, which must be maintained in order to ensure a continuous supply of healthy blood. Given the success of proteasome inhibitors for AML, the primary objective of experiments described in this grant application is to determine whether such drugs can also be used to destroy CML stem cells. If successful, proteasome inhibitors are likely to provide a promising new therapy for patients with CML.