Uncovering mechanisms of DNMT3A stability in hematologic malignancies
Taishi Yonezawa
PhDBaylor College of Medicine
Project Term: July 1, 2023 - June 30, 2026
DNMT3A is a critical tumor suppressor in hematologic malignancies; DNMT3A protein levels affect both tumor latency and type. DNMT3A is regulated in part by protein stability, but the mechanisms remain incompletely understood. Here, I will dissect the mechanisms that regulate DNMT3A protein turnover using CRISPR screening and genetically engineered mouse leukemia models. This work will reveal whether its stabilization could contribute to a new therapeutic approach for hematologic malignancies.
We are interested in a protein called DNA methyltransferase 3A (DNMT3A), which plays an important role in the production of normal red blood cells, white blood cells and platelets. Mutations in the DNMT3A gene are common in blood cancers, revealing that it has a crucial job, when present, to prevent blood cancers; thus, it is considered a “tumor suppressor”. DNMT3A mutations can be found in the blood cells of individuals years before they develop cancer, indicating these mutations predispose individuals toward the development of leukemia or lymphoma. The goal of my project is to better understand how DNMT3A is regulated, so that we can manipulate its level with the goal of developing new therapeutic approaches. Our recent study has shown that many blood cancer-related DNMT3A mutations down-regulate its expression at the protein level, and as a result, these mutations led to decreased DNMT3A function. Our preliminary evidence suggests a possibility for modulating dosage of DNMT3A protein expression to treat blood malignancies. Our previous studies also identified one of the clues to maintaining DNMT3A level, which is that the DNMT3A protein is constantly degraded. We hypothesize that understanding the mechanisms of DNMT3A protein degradation will be useful to develop a new therapeutic approach for blood cancers, if we can identify a strategy to prevent its degradation. However, the mechanisms of DNMT3A protein stability remain incompletely understood, and it is uncertain whether our finding can be useful at the animal and clinical level. Therefore, in this proposal, we will uncover mechanisms regulating DNMT3A stability and evaluate its function using high-throughput screening. The screening will enable us to observe DNMT3A protein expression and to identify a modulator which is involved in its regulation. Furthermore, we will establish mouse leukemia models with unstable Dnmt3a. We will increase DNMT3A protein expression in the mouse models to determine whether their survival is prolonged. Moreover, we will examine adverse events and dose design for their treatment. If successful, we aspire to develop DNMT3A stabilizers for future clinical use to improve outcomes for patients with DNMT3A-mutant hematopoietic malignancies. These studies will shed light on mechanisms regulating the protein stability of DNMT3A and may reveal new a treatment strategy for some blood cancer patients.