The biological and therapeutic consequences of SF3B1 mutations in myelodysplastic syndromes
Fred Hutchinson Cancer Research Center
Project Term: July 1, 2017 - June 30, 2022
My lab studies how common mutations affecting RNA splicing, a critical step during expression of most human genes, give rise to myelodysplastic syndromes, leukemias, and other malignancies. We combine experimental and computational studies to create new models of these disorders and thereby understand their molecular origins. In the long term, our goal is to identify new therapies for treating these disorders, which currently have limited treatment options.
Myelodysplastic syndromes (MDS) are a group of blood disorders characterized by impaired differentiation of hematopoietic stem cells into functional blood cells. MDS frequently has a poor prognosis and is associated with a high risk of transformation into acute myeloid leukemia. There are few treatment options for MDS, largely because the underlying molecular changes that drove MDS were not known until recently. Recent genome sequencing studies revealed that MDS and related diseases are associated with specific mutations (genetic changes) in hematopoietic stem cells. These mutations most commonly affect genes that control a molecular process termed "RNA splicing." RNA splicing is critical to the process by which genetic information in DNA is "read" to make proteins. We now know that MDS-associated mutations that affect RNA splicing cause mistakes during the transfer of genetic information from DNA to protein. However, we do not yet know precisely which mistakes ultimately give rise to MDS. We plan to use both experimental and computational methods to determine how mutations that affect RNA splicing give rise to MDS. Understanding the specific molecular changes that occur in MDS cells carrying these mutations will enable us to identify potential new therapeutic opportunities for treating MDS. Because the same mutations affecting RNA splicing are found in other blood diseases as well, such as chronic lymphocytic leukemia, we hope that our discoveries will improve the treatment of many different blood diseases.