Mutations in the Spliceosomal Gene ZRSR2 in Myelodysplastic Syndromes
Abstract
Background: Myelodysplastic syndromes (MDS) are a group of blood disorders in which the bone marrow fails to make adequate numbers of various types of blood cells. MDS is the most common class of acquired bone marrow failure syndromes in adults; the disease affects primarily the elderly, and incidences are expected to rise with aging of the population, suggesting that within a few years MDS will become a major healthcare challenge. Yet, current therapies for MDS continue to be unsatisfactory. A major obstacle in the development of new treatments is an incomplete understanding of the causes behind MDS onset and progression. One of the most exciting recent discovers by us and others has been the identification of recurrent mutations in genes encoding RNA splicing factors in the bone marrow of ~60% of MDS patients. RNA splicing is a process occurring when genetic information in the DNA is converted into proteins. Splicing factor mutations are mostly specific to MDS, suggesting that a better understanding of RNA splicing dysregulation in MDS will lead to an overall better understanding of the pathogenesis and open new therapeutic avenues. Four genes (SF3B1, SRSF2, U2AF1, and ZRSR2) harbor the bulk of splicing factor mutations in MDS, which are mutually exclusive, and are associated with specific downstream molecular and clinical features. Several groups have recently begun to characterize the effects of dysregulation of the three most frequently mutated splicing factor genes (SF3B1, SRSF2, and U2AF1) on normal blood cell development and RNA splicing alterations. Our studies focus on ZRSR2, the fourth most commonly mutated splicing factor gene in MDS. To our knowledge, our group is the only one closely studying ZRSR2 in MDS. In preliminary work, we showed that silencing ZRSR2 in human blood cells impairs their proliferation and maturation. Remarkably, we found that bone marrow cells from patients with ZRSR2 loss of function mutations, as well as laboratory MDS cell lines with ZRSR2 knockdown, display RNA splicing alterations in a group of genes that contain specific introns (introns are sequences of RNA removed during normal splicing of RNA to make a protein), called U12 introns. Significance of U12-type intron splicing was recently underscored by studies linking defects in this pathway to human disease. Although the discovery of splicing factor mutations in MDS suggests a new paradigm for MDS development, the pathological functions induced by these mutations are not well defined. In particular, how ZRSR2 mutations lead to MDS is largely unknown and is the major focus of this project. Hypothesis/Objectives: We hypothesize that splicing factor gene mutations lead to MDS by altering the splicing of specific important genes and that identifying these genes along with their cellular pathways will help develop novel therapeutic strategies for MDS. Our objective is to identify key mis-splicing events in ZRSR2 mutated cells and to link these events to MDS pathogenesis. Innovation: The innovation of this study is based on a combination of advanced experimental and computational approaches including ones not previously used in MDS cells with splicing factor mutations. To this end, we have established new reagents including genetically engineered human and mouse cell models with silencing of ZRSR2. Additionally, we obtained previously undescribed MDS patients samples with and without ZRSR2 mutations. These novel tools will allow us to perform a rigorous analysis and determine how ZRSR2 mutations give rise to MDS. Our findings hold a genuine potential to provide novel insights and fundamentally advance our understanding of the pathogenesis of MDS. Impact: In the short term, the proposed study could be of great scientific importance in elucidating the role of aberrant splicing in MDS. In the long term, this basic research study could serve as the foundation for the development of novel therapeutic agents for M
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710093
Entities
People
- H. Phillip Koeffler
Organizations
- Cedars-Sinai Medical Center
- United States Army