Grant: Project Grant

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the most frequent cause of death from cancer before age 20 in North America. The main focus of this application is T-cell acute lymphoblastic leukemia (T-ALL), a high-risk leukemia affecting children and young adults. Current T-ALL treatments entail high-dose multi-agent chemotherapy, leading to cure rates of 80% in children and 60% in adults. However, a large number of patients still relapse, and refractory or relapsed patients remain very difficult to treat. Another limitation of current therapies is the severity of secondary effects resulting from chemotherapy treatments, that can lead to stunted growth and reduced quality of life. Thus, there is an urgent need to develop precision therapies that are both more efficient and less toxic to target specifically the oncogenic proteins responsible for disease while preserving healthy cells. Recently, we have obtained results suggesting a new mechanism through which the oncogenic protein TLX1 induces and maintains leukemia. Specifically, we found that TLX1 perturbs interactions between genes in leukemic cells. Such disruption leads to rearrangement of the gene expression program, block in differentiation and development of leukemia. In this application, we will use state of the art molecular approaches to resolve the mechanism through which TLX1 rearranges the topological organization of the genome. We will also use in vivo models of disease to test for new therapeutic approaches based on targeting TLX1-mediated aberrant loop formation in the genome. Thus, successful completion of this proposal is expected to identify new therapeutic targets that could be used to treat leukemia patients while having fewer side effects.