Exploiting Epigenetic Dependencies of Notch1 for Clinical Benefit

Background
Leukemia is a cancer of the blood, which often starts when chromosomes in the blood cells break and cause blood cells to grow in a disordered and uncontrolled manner. Our research group is studying a gene responsible for Mixed Lineage Leukemia (MLL1), also named MLL1, which is commonly broken in leukemia of very young children. Our investigations have shown that the MLL1 gene controls stem-cell like pathways that may be involved in other types of childhood leukemia that do not have breakage of the MLL1 gene. Specifically, we discovered that the MLL1 gene helps another leukemia protein called NOTCH1 function. NOTCH1 is over-active in over 60% of a certain type of childhood leukemia involving immune cells called T cells. Normal T cells do not need the MLL1 protein whereas T cell leukemia resulting from NOTCH1 malfunctions are dependent upon MLL1.

Project Goal
We propose to test new small molecule drugs developed by our collaborator at University of Michigan to better eradicate T cell leukemia. We will combine sophisticated genetic models, molecular and genomic experiments and this new class of compounds to target MLL1 at the same time as NOTCH1 targeting compounds. These studies will determine how these two proteins work together and how we can target their aberrant activities in T cell leukemia to improve cures without damaging other developing tissues in young patients and provoking long-lasting side effects.