Identification and Characterization of an Epigenetic Program that Maintains the Self-Renewal of MLL Myeloid Leukemia Stem Cells

Traditional approach targeting only genetic factors and non-cancer stem cells for drug discovery appears insufficient to combat cancer diseases especially in the category of childhood leukemia caused by MLL gene mutation which occurs frequently in infants and children and associates with poor survival rate. It is becoming clear that cancer cells transformation is initiated and maintained by both genetic and epigenetic mechanisms. Epigenetic therapy has been emerged as a promising treatment of cancer diseases because epigenetic alterations, unlike genetic mutation, are reversible by pharmacological manipulation. However, development of effective targeted epigenetic therapy is still in its infancy because a comprehensive understanding of epigenetic mechanism controlling cancer cells malignancies is still lacking.  Similar to other cancer diseases, Leukemia is also initiated and sustained by a sub-fraction of leukemia stem cells (LSCs) which possess aberrant self-renewing ability and thus even a single leukemia stem cell is able to induce disease relapse. Hence, LSCs must be specifically targeted and eradicated in order to have permanent cure. To achieve such an objective, our group has successfully defined and characterized a subset of LSCs in a mouse model of human MLL leukemia. This valuable in-vivo model system provides a unique opportunity in this project to investigate epigenetic mechanism in maintaining LSCs self-renewal property. Comprehensive epigenetic data obtained from global 'epigenome-wide' study in this project will set a foundation for epigenetic drug development to cure this category of aggressive childhood leukemia in near future.