Identifying Mechanisms of Glucocorticoid Resistance in Pediatric Acute Lymphoblastic
Leukemia is a blood cancer that results from the overproduction of immature white blood cells in the blood and bone marrow. Treatment for childhood acute lymphoblastic leukemia (ALL) consists of several chemotherapeutic agents and the glucocorticoid prednisolone or dexamethasone. Although treatment is effective in curing most children, 20-30% of pediatric patients fail to respond to treatment or relapse during or following treatment. Patient response to dexamethasone has proved to be a reliable prognostic indicator; that is patients that fail to respond to dexamethasone exhibit a poor overall survival.
The goal of the work proposed is to understand the molecular and cellular basis of dexamethasone resistance with the long-term goal to develop therapies for children who relapse. To identify the genes/pathways that mediate resistance, we have conducted a genome-wide shRNA screen in dexamethasone sensitive mouse leukemia cells. Genes that contribute to dexamethasone resistance were identified and are currently being validated in relapsed patient samples. We will also determine whether the genes/pathways identified predict dexamethasone response in diagnostic leukemia patients. Determining how leukemic cells become resistant to dexamethasone will allow us to predict which patients may fail treatment and aid in the development of novel therapeutics for relapsed leukemia patients.