Myelodysplastic syndromes (MDS) are a heterogenous group of clonal blood disorders characterized by ineffective differentiation of stem cells to produce blood. MDS usually has a poor prognosis and patients are at elevated risk for disease transformation to acute myeloid leukemias. Because the genetic and molecular aberrations that give rise to MDS were unknown until relatively recently, there are few treatment options for MDS.
The most common cause of MDS is a genetic mutation occurring in blood cells that affects a process called “RNA splicing.” RNA splicing is a molecular process that is critical to the means by which genetic information encoded in DNA is used to make proteins. The most commonly mutated RNA splicing factor gene is called SF3B1. We now know that many patients with MDS carry mutations in SF3B1, but we do not have a good understanding of why these mutations cause disease.
We propose to determine how mutations in SF3B1 cause MDS and potentially create new opportunities for treating this disease. In particular, we will study how SF3B1 mutations disrupt a biochemical complex called the non-canonical BAF complex, which is involved in chromatin remodeling, and plays an important but incompletely understood role in hematologic malignancies. We will also determine whether it is possible to restore normal function of the non-canonical BAF complex as a potential therapeutic for treating hematologic malignancies with SF3B1 mutations.