The Role of Mutant U2Af1 in the Pathogenesis of Myelodysplastic Syndromes
Abstract
My future career goal is to become a research scientist and professor at an academic institution, focusing on cancer research. The Peer Reviewed Cancer Research Program Horizon Award funding will give me the opportunity to conduct genetic cancer research as part of my PhD training in Dr. Matthew Walter s laboratory, preparing me for a career in genetic cancer research. During my training, I will acquire both technical and intellectual knowledge required to complete the proposed project and executing future projects as a genetic cancer researcher. In addition to research, teaching and mentoring experiences are critical for my future career. I have acquired teaching experience as a Teaching Assistant for a Biology class at Washington University, and I will have an opportunity to mentor undergraduate students during the summer in Dr. Walter s laboratory. After a successful completion of this proposed research project, I plan to share my findings with the general public and scientific community. I will present my work in at least one national scientific conference per year, including the American Society of Hematology and/or the American Association for Cancer Research annual meetings. I also plan to publish the results in a peer-reviewed scientific journal. The presentation and writing experience I will gain during this project will be invaluable hands-on experience in communicating my scientific work to the general public and scientific community, both of which will prepare me for my future career. My proposed research is aimed to study how mutations in a group of genes involved in splicing or processing of genetic material contribute to development of myelodysplastic syndromes (MDS), a blood cancer. MDS are the most common adult blood cancer in the United States. Currently, stem-cell transplant is the only therapy with curative potential for MDS. However, this therapeutic approach is not ideal due to toxicities from the transplant, especially for the patients over 60 years old. Therefore, novel and more effective therapies are needed. Our goal is to understanding the genetic mechanisms underlying MDS development using genetic cancer research, a key for the long-term development of novel treatment options. Up to half of patients with MDS have a mutation in a gene that control splicing of genetic material together, making them the most highly mutated class of genes in this disease. We are particularly interested in mutations in the gene U2AF1, which is associated with an increased risk of progress from MDS to a more severe secondary acute myeloid leukemia (AML). We have developed a mutant mouse model to study the role of the mutation in the disease development. While this mouse develops some characteristics of MDS such as low white blood cell counts, it does not fully develop MDS. We think that mutations in other genes are required in addition to U2AF1 mutations in order for the full disease to develop. In this project, we will determine whether mutation in another gene called ASXL1, which is mutated in the same cells having a U2AF1 mutation, cooperates to induce full-blown MDS or AML. Both mutant genes would be ideal therapeutic drug targets if they do cooperate to cause MDS. Identifying genetic mutations that contribute to MDS initiation is key to developing effective treatments. In addition, the mouse models developed in this project will be valuable reagents for the research community to test drugs in future studies. Therefore, findings from this project could help older patients who develop MDS, including Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610506
Entities
People
- Brian A. Wadugu
Organizations
- United States Army
- Washington University in St. Louis