MLL Oncogene-Dependent Enhancer Reprogramming Promotes Leukemogenesis
Rearrangement of the MLL gene (MLLr) is one of the most commonly recurring genetic events in acute myeloid leukemia (AML) associated with poor prognosis and survival. Our published and preliminary data have described key features of MLLr leukemia and shown that leukemia cells form a functional hierarchy wherein a minor group of cells serves as functional leukemia stem cells (LSCs). LSCs undergo self-renewal and are responsible for disease maintenance, resistance and relapse. Thus, LSCs would be a key target for therapeutic intervention. Emerging whole-genome sequencing data provide an unprecedented view of AML with aberrant genomic and/or epigenetic architecture, leading to dysregulated gene expression. As non-coding regulatory DNA sequences, enhancers control the expression of other genes. Together with increasingly recognized roles of these gene regulatory elements in the AML development, it is necessary to determine the role of master gene regulatory elements in leukemia stem cell function.
I will test the hypothesis that the pathogenic gene expression programs in leukemia stem cells are driven by aberrant activity of these regulatory elements.