Identifying Therapeutic Vulnerabilities in Pediatric AML through Investigation of the MECOM Transcriptional Network
Pediatric acute myeloid leukemia (AML) is an aggressive cancer of the blood that despite very intense treatment can be very difficult to cure. In particular, a subset of AML characterized by genetic changes affecting a protein called MECOM have very poor outcomes. MECOM is also a critical regulator of normal blood stem cells that helps maintain stem cells throughout an individual?s life. High MECOM levels in AML confer stem-cell like properties to AML cells and make them more resistant to standard treatment and more likely to relapse. In prior work, I investigated the function of MECOM in stem cells and uncovered an essential gene network controlled by MECOM that maintains stem cell properties. When I studied AML samples from almost 1000 patients, I found that those AML patients with dysregulated MECOM genes had significantly worse clinical outcomes and that dysregulation of this set of genes occurred even in AML without excess levels of MECOM itself. This observation suggests that there are other critical regulators of this essential gene program that can be targets of future drug development. When I studied these genes in AML cells, I found evidence that two other proteins may compete with MECOM to control expression of this important gene network. A better understanding of the cellular signals that control expression of these genes will lead to a better ability to predict patient prognosis and will allow us to specifically interfere with this signaling to develop more targeted, safe, and effective treatments for this highly aggressive disease.
Project Goal:
MECOM signaling in pediatric AML controls an important network of genes that make a subset of AMLs very difficult to cure. I have found that disruption of MECOM in AML cells leads to loss of leukemia stem cells but because of its protein structure, developing drugs specifically against MECOM is very challenging. In this proposal, my goal is to uncover the specific role of MECOM in controlling this important gene network to identify other proteins that could be easier to manipulate with treatments. To do so, I have used a cutting-edge strategy to engineer MECOM-addicted AML cells with a MECOM kill-switch that will allow me to specifically destroy the MECOM protein in a matter of minutes. This will allow me to uncover the immediate, specific effects of MECOM loss on the structure of DNA loops and expression of other genes. Specifically, my prior work suggested that two proteins, RUNX1 and CTCF, become differentially activated upon MECOM loss and this strategy will allow the investigation of these interactions. In the second aim, I will systematically investigate each gene of the MECOM network in AML to uncover which specific downstream genes are necessary for MECOM activity in AML. One gene of the MECOM network in particular has already shown promise as an essential effector of the MECOM network, and I will specifically investigate its function in AML. In addition, I will develop a specific method to block this gene product that, if successful, could be adapted for use in pediatric AML patients.
