Therapeutic Targeting of Spliceosomal-Mutant Acquired Bone Marrow Failure Disorders
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by inefficient blood production. MDS represents the most common cause of acquired bone marrow failure in adults. There are few effective therapies for the majority of MDS patients. An important reason that relatively few therapies are available is that we have an incomplete understanding of why and how MDS develops. In 2011, researchers discovered that most patients with MDS carry genetic mutations that spontaneously developed in the bone marrow, ultimately affecting a molecular process called RNA splicing. RNA splicing is the process wherein genetic information is read from DNA and then used to make proteins. However, despite these research breakthroughs in determining the set of spontaneous genetic mutations that are associated with MDS, we do not yet fully understand why abnormal RNA splicing results in MDS. Moreover, we do not yet have therapies that specifically target MDS cells bearing this common class of mutations. Thus, the goals of this proposal are twofold: (1) to determine how spliceosomal gene mutations result in development of MDS in more detail and (2) to develop new therapies specifically aimed at eradicating MDS cells that carry spliceosomal gene mutations. We hypothesize that spliceosomal gene mutations cause MDS primarily by affecting the splicing of a relatively small number of very important genes and that identifying these particularly important genes will allow us to develop new treatments for MDS. To accomplish our goals and test these hypotheses, we propose to use a combination of experimental and computational approaches. We will determine how mutations that affect RNA splicing give rise to MDS. We will then use this knowledge to design and initiate drug discovery screens, wherein we will test thousands of molecules for the ability to selectively target and kill MDS cells carrying these mutations. The innovative aspects of this proposal include the use of drug and genetic screening technologies that we will apply to look for ways to selectively target splicing mutant cells. The experiments described in this proposal will use a number of novel and previously undescribed genetically engineered tools that we have already developed for our MDS research. In addition, we will combine the expertise of two scientists with different but complementary expertise. This includes a physician-scientist with a long-standing interest in understanding MDS (Dr. Abdel-Wahab) and a basic scientist with a very strong background in genomics and splicing (Dr. Bradley). We are combining our collective knowledge, expertise, and intellectual resources of our two institutions (Memorial Sloan Kettering Cancer Center and Fred Hutchinson Cancer Research Center) in hopes of developing new approaches to understand and treat MDS. We expect our research to further our understanding of how MDS develops and ultimately to lead to the identification of new drugs and therapeutic approaches for treating MDS. If successful, this proposal could have tremendous therapeutic impact for patients with bone marrow failure due to MDS. Finally, spliceosomal gene mutations are also encountered in patients with related cancers such as acute myeloid leukemia. Thus, there is a possibility that the treatments identified in our studies of MDS could actually help an even broader category of blood cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1610059
Entities
People
- Omar Abdel-Wahab
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army