Discovery of Inhibitors of MLL Fusion Proteins as Targeted Therapies for Pediatric Acute Leukemia
Acute lymphocytic leukemia (ALL) strikes 2,500 children per year in the United States alone. For many, ALL is curable, with overall survival approaching 90%. However, 10% of childhood ALL remains difficult to treat, and there is little scope to increase the dosage of chemotherapy, which was developed to treat adult cancer and is highly toxic to children. Thus there is a pressing need to develop novel treatments targeted specifically at pediatric cancer. Many of the most difficult to treat childhood leukemias are triggered by rearrangement of the gene MLL (mixed lineage leukemia). MLL rearrangements are very common in infant leukemia, where they are found in 80% of patients. These infants have an especially grim prognosis: a five-year survival rate of barely 40%. MLL rearrangements disrupt the normal control of gene expression. So-called progenitor cells fail to undergo normal differentiation into specific types of blood cell; instead, they acquire the ability to proliferate unchecked. It is this acquired capacity for 'self-renewal' that is one of the key triggers for acute pediatric leukemia. MLL rearrangements trigger the onset of leukemia through a complex of proteins (transcriptional activators) that have been shown to be essential to the proliferation and survival of leukemic cells. Our goal is to use high-throughput chemical library screening to discover inhibitors of protein binding that disrupt the MLL-linked protein complex in vivo. Optimization of these inhibitors for anti-leukemic potency should lead to the development of targeted molecular therapies for childhood leukemias that harbor MLL rearrangements.
