Molecular Regulation of CNS Involvement in Pediatric ALL
T cell acute lymphoblastic leukemia is a common pediatric tumor caused by the transformation of T cells of the immune system. Although treatment outcome in T-ALL has improved in recent years, patients with relapsed disease continue to have dismal prognosis despite the use of protocols involving hematopoietic stem cell transplantation. One of the most devastating manifestations of the disease is the leukemia relapse in the central nervous system (brain and spinal cord). It is thus very important to identify and study the genes that control both induction and establishment of the disease. Recent compelling evidence demonstrated that activating mutations in one gene (Notch1) are the oncogenic trigger for the vast majority of T-ALL patients. However, we know very little about the molecular mechanisms of Notch1-induced T cell oncogenesis. In this grant we identify a new gene-target of Notch1, the chemokine receptor CCR7, that appears to be essential for the metastasis of tumor cells in the central nervous system (CNS). Using molecular biology techniques, animal modeling and whole-body imaging we study the mechanism of CCR7 gene expression in T-ALL. Also, we generate animal models of the human disease and use them to screen drugs that can block CCR7 expression and CNS infiltration. These studies are of unique clinical importance as they directly try to both understand the biology of leukemia but also identify new treatments for the disease. They can also be rapidly translated to human T-ALL therapy as the drugs that we test have been already approved by the U.S. Food and Drug Administration (for the treatment of different cancers). We thus believe that we could target CNS infiltration and leukemia and quickly pass from the bench to the clinic.