Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders characterized by ineffective and dysplastic hematopoiesis. There are few effective treatments for MDS, due in part to our incomplete understanding of the molecular basis of this disease. The recent discovery of high-frequency mutations affecting the RNA splicing machinery in MDS presents a significant opportunity to further our knowledge of MDS biology and inform the development of new therapeutics. However, the molecular consequences of spliceosomal mutations are unknown, hindering efforts to understand how these mutations contribute to dysplastic hematopoiesis and lead to new therapeutic opportunities. To address this gap in knowledge, we propose to determine the mechanistic, functional, and therapeutic consequences of mutations affecting the spliceosomal gene U2AF1, one of the most commonly mutated genes in MDS. Our team consists of a basic scientist with experience in RNA splicing mechanisms and splicing- based therapeutics (Bradley) and a physician-scientist with experience in MDS biology and patient care (Shimamura). In preliminary studies, we determined how MDS-associated mutations alter U2AF1's normal role in 3' splice site recognition and identified molecular abnormalities in U2AF1-mutant cells. We propose to build on these preliminary studies with the following aims:
Aim 1, Determine the mechanistic basis and consequences of the observed genetic spectrum of U2AF1 mutations;
Aim 2, Determine how U2AF1 mutations dysregulate downstream molecular pathways, contributing to molecular features of dysplastic cells;
Aim 3, Identify potential therapeutic opportunities for targeting U2AF1-mutant cells. The significance of these studies is that they will determine the molecular consequences of U2AF1 mutations and give insight into how spliceosomal mutations promote MDS. The health relatedness is that the proposed research may identify opportunities for selectively killing cells with U2AF1 mutations.
Over 10,000 individuals are diagnosed per year in the United States with a myelodysplastic syndrome, a group of blood diseases for which few treatments are available. As disease incidence is expected to increase with the aging of the population, there is a public health need to further our understanding of these diseases and develop improved therapies. We propose to study mutations affecting components of the RNA splicing machinery to discover molecular changes that drive myelodysplastic syndromes and identify potential new therapeutic targets.
