Targeting polycomb-mediated epigenetic silencing in T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of white blood cells which affects both children and adults. Many children with T-ALL can be cured with very intensive chemotherapy, but there are significant long term health problems associated with this therapy. A major goal for T-ALL is to develop new therapies that can help reduce the burden of treatment and offer cures to the approximately 20% of pediatric patients who succumb to the disease. Developing these new treatment strategies depends critically on understanding what makes normal blood cells become malignant, and what keeps the cancer cells alive and growing. Identifying certain genes that are damaged in many cases of T-ALL cell has helped scientists develop mouse models of the human disease. These models provide a useful tool for testing our ideas about the causes of T-ALL, and also for testing whether treating those causes may provide promising new therapeutic strategies. In this proposal, we describe a method for using a mouse model of T-ALL to investigate whether the leukemia cells abnormally prevent some of their genes from working properly, even though the genes themselves are not damaged, through a mechanism called gene silencing. If we find that genes important in cell development and survival are being inappropriately silenced in T-ALL, it may be possible to kill the tumor cells by reversing that silencing.