Grant: Operating Grant

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer occurring in children and adults wherein cells belonging to the immune system acquire a defect in their normal regulatory circuitry and grow in an uncontrolled manner. Intensive chemotherapy treatments lead to survival rates of 70% in children and 35% in adults. Furthermore, current treatments are associated with acute and chronic debilitating toxicities and very few options are available for refractory and relapsed patients. Therefore, there is an urgent need to develop novel, targeted approaches that are both more efficient and less toxic. Through a detailed analysis of the mechanism of leukemia maintenance in a specific subtype of T-ALL representing approximately 50% of all cases, we have recently identified a disproportionate sensitivity of this subtype towards a particular drug that targets the protein at the origin of the oncogenic transformation. Furthermore, we have validated this novel potential therapy in patient-derived transplantation models of leukemia. In the current proposal, we will study the molecular mechanism of leukemia maintenance in the remaining three major subtypes of T-ALL. These studies are expected to identify subtype-specific vulnerabilities to drugs for each T-ALL subtype that will then be tested in mice transplantation models of human leukemia. These approaches are expected to lead to the development of novel, targeted therapies for treating children and adults affected with this deadly disease.