Grant: Operating Grant

It is news no parent wants to hear: your child has leukemia. While advances in treatment mean that most children now survive this cancer of the bone marrow this is not the case for an unfortunate few, for whom the likelihood of successful treatment is as low as 10 per cent. Several of these leukemias are caused by a mutation that affects a protein known as mixed-lineage leukemia (MLL). Not just a disease in children, MLL leukemia also crops up in adults, likely as a result of genetic mutation caused by drug treatments. The goal of this proposal is to study how the activity of MLL is regulated, to understand its shape and how it functions in its diseased and normal states. Normally, the protein works to control genes important during development. In a diseased states, the activity of MLL1 become uncontrolled which in turn activate a cascade of events leading to leukemia. Consistent with its important biological roles, the activity of MLL is highly regulated and mediated by an intricate network of proteins forming a complex of 15 subunits all playing key roles in controlling MLL1 functions. In understanding the protein structures of these regulatory proteins with MLL1, this research programs will help to develop ways to interfere with interactions that cause disease, while preserving those needed for normal functioning. Because MLL also functions in part as an enzyme, this project connects well with our long-term goal of understanding how structure and chemistry come together to create the high specificity of these catalytic proteins. More than just leading to potential treatments for this deadly form of leukemia, this project could also lead to potential applications in areas related to developmental biology.