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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103854-03
Application #
9392553
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bishop, Terry Rogers
Project Start
2015-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Dvinge, Heidi; Kim, Eunhee; Abdel-Wahab, Omar et al. (2016) RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 16:413-30
Fei, Dennis Liang; Motowski, Hayley; Chatrikhi, Rakesh et al. (2016) Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival. PLoS Genet 12:e1006384
Lee, Stanley Chun-Wei; Dvinge, Heidi; Kim, Eunhee et al. (2016) Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med 22:672-8
Inoue, Daichi; Bradley, Robert K; Abdel-Wahab, Omar (2016) Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis. Genes Dev 30:989-1001