Grant: Operating Grant

One third of childhood cancers are leukemias, with Acute Lymphoblastic Leukemia (ALL) accounting for 80% of childhood leukemias. Although improvements in chemotherapy have resulted in an 80% treatment success rate, acquired drug resistance remains a key obstacle to the treatment of the remaining 20%. A major mechanism for relapse of leukemia results from the few tumor cells hiding in the bone marrow compartment which acquire drug resistance and become resistant to further treatment by chemotherapy. Furthermore, the highest risk for ALL occurs during the critical developmental ages of 2 to 5 years. Administration of high dosage chemotherapy dramatically increases the likelihood for serious developmental complications even for survivors of childhood ALL. New strategies to improve ALL outcomes are urgently needed and crucial for the wellness of our children. This proposal will investigate the causes contributing to acquired drug resistance in childhood leukemias. Specifically, one involving cell adhesion termed Cell Adhesion Mediated Drug Resistance (CAMDR). Cell adhesion is the binding of a cell to cellular matter outside of the cell. This binding is known to trigger the tumor cell's ability to tolerate drugs that would normally kill it. We will focus on the cell adhesion protein named alpha4 integrin in the development of CAMDR. Alpha4 integrin has been shown to convey enhanced chemotherapeutic drug resistance in several types of blood cancers including ALL, Acute Myelogenous Leukemia and Multiple Myeloma. Thus far, the role of alpha 4 integrin in development of relapse in leukemias has not been well studied. This proposal investigates the causes underlying leukemic drug resistance and to identify the molecular targets to achieve higher efficacy chemotherapy.