Discovering the function and targeting dysregulated nuclear condensates in myeloid leukemia
Michael Kharas
PhDMemorial Sloan Kettering Cancer Center
Project Term: October 1, 2022 - September 30, 2025
Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for acute myeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsing with their disease. Our studies have a uncovered a new nuclear structure that is dysregulated in myeloid leukemia. This proposal studies the identity and function of this nuclear body in human AML and strives to identify novel therapeutic strategies and targets in leukemia.
Acute myeloid leukemia is a heterogeneous set of diseases that remains a challenge to treat effectively resulting in the leukemia cells returning after treatment. One of the hallmark features of myeloid leukemia is a failure for the cells to properly differentiate into normal immune cells. This block in development can be controlled by many intrinsic cellular factors. RNA molecules comprise the information that is the intermediary between genes and proteins. An emerging focus of study is how these RNA molecules may be involved in disease processes. Our laboratory and others have identified that there are specific RNA binding proteins that regulate how genes are controlled. Recent studies have found that RNA can become marked with a chemical modification called methylation that can act as a signal that can be read by specific proteins. This pathway has been shown to be of therapeutic interest as companies have begun developing inhibitors to target the enzymes that place these marks, the erasers and the readers. We found that one of the proteins called YTHDC1 can form a new nuclear structure by binding to these signals. Additionally, these structures are increased in leukemia cells compared to normal blood cells. We propose that these altered nuclear bodies act dynamically and can control which genes can be turned on and off or can protect cancer causing RNAs from being destroyed. This proposal studies these new nuclear bodies to identify how they are regulated and what is their composition. We will identify new therapeutic strategies to target these nuclear bodies.