Mechanisms of Oncogenic Transformation by TLX1/HOX11

More children die from acute lymphoblastic leukemia (ALL) than any other cancer. About one-third of patients develop serious side effects (such as another cancer) as a consequence of treatment. We need to better define the molecular origins of ALL to develop new medicines that are more effective and less toxic. Many ALLs arise from T-cells. About one-third of patients with T-cell ALL carry a cancer gene called TLX1. Mice in which scientists have artificially removed the TLX1 gene are healthy. Thus, TLX1 is an attractive drug target. Blocking TLX1 should spare normal healthy tissue. After two years of development, we have developed a new mouse model in which TLX1 can be turned "on" or "off." When TLX1 is turned on, our mice develop leukemia. When TLX1 is turned off, the leukemia grows more slowly. We are the first to show that TLX1 is important to both start and sustain leukemia. We now want to find ways to kill these leukemia cells. To do this, we must first figure out how TLX1 changes normal T-cells into leukemia cells. Does it make the cells proliferate faster? Does it cause the cells to survive better? We will determine all of these changes. We will then scan the human genome to find the genes that are controlled by TLX1. We will then connect these genes to each of these changes. These genes will help us identify new therapeutic targets in ALL to advance our understanding of this terrible disease and improve current medicines.