New York University School of Medicine
Project Term: July 1, 2017 - June 30, 2022
We are investigating the mechanisms by which microRNAs regulate stem cells in acute myeloid leukemia (AML). We are utilizing patient cells and mouse models of AML to determine if microRNAs regulate leukemia stem cells by virtue of their presence in different parts of the cell (cytoplasm vs nucleus). Given the important role of microRNAs in AML , better understanding how microRNAs regulate leukemia stem cells will identify novel targets for therapy.
Acute myeloid leukemia (AML) is composed of two populations of cells with differing characteristics. The bulk population directly gives rise to the disease symptoms. The second population is very small and is composed of leukemia stem cells (LSCs), whose role is to initiate disease and generate the AML bulk population. These self-renewing LSCs are therapy resistant and mediate disease relapse; therefore, it is critical to understand the mechanisms that regulate LSCs in order to develop strategies designed with the intent to cure. The characteristics of all cells are determined by DNA contained in the nucleus of the cell. The information DNA provides is converted to RNA, which is exported out of the nucleus into the cytoplasm of the cell, where the cell’s proteins are produced. Small RNA molecules, called microRNAs (miRNAs) regulate the expression of protein-encoding genes in cells. My laboratory has shown that miRNAs can regulate normal blood stem cell function, promote the development of AML, and regulate LSCs. We have shown that two nearly identical microRNAs are frequently overexpressed in LSCs, but it is unclear what their relative contributions are to regulating leukemia cell survival and LSC function. We hypothesize that these two microRNAs can serve overlapping but non-redundant functions due to differences in their location within the cell. Indeed, while most miRNAs are thought to function in the cytoplasm of the cell, some microRNAs enter the nucleus, and we predict that such a nuclear distribution will affect their ability to regulate genes critical for LSC function. Leveraging our expertise in LSC biology, as well as novel technologies that we have either developed or optimized, we seek to better understand the role of these critical miRNAs in AML disease initiation and maintenance. Thus, we propose to: 1) Determine whether structurally similar microRNAs play similar or unique roles in LSCs; 2) Determine whether the subcellular location of microRNAs dictates their ability to regulate LSC function; and 3) Identify the genes that these microRNAs regulate, specifically in LSCs. Overall, we expect to not only reveal how microRNAs regulate LSCs but also to provide general insights into how microRNAs can differentially regulate gene expression based on their position within a cell. These investigations may lead to a better understanding of AML and may provide avenues for novel therapeutic approaches.