
Researcher Profiles

Mounica Vallurupalli, M.D.
2023 Funding recipient
Defining the mechanistic implications of SF3B1 mutations in myelodysplastic syndromes
EvansMDS Young Investigator Award
PROJECT SUMMARY
Myelodysplastic syndromes (MDS) are disorders resulting from genetic alterations in bone marrow stem cells that impair blood cell development and production. Genetic alterations in splicing factor genes (SF3B1, U2AF1, SRSF2, ZRSR2) arise in bone marrow stem cells over the course of one’s lifetime. Splicing factors are responsible for properly piecing together mRNAs which are necessary to make proteins in a cell. Alterations in these genes give rise to dysfunctional mRNA production. We have known for the past decade that these alterations contribute to the development of myelodysplastic syndrome (MDS) by impairing the proper production of blood cells from bone marrow stem cells. Yet, we do not understand how these mutations impair blood cell production and have no effective targeted therapies for patients with these alterations.
The most altered gene of this class is SF3B1. Mutations in SF3B1 impair red blood cell production causing severely low red blood cell counts or anemia. This proposal will develop new models of SF3B1-altered MDS after introducing these mutations into human bone marrow stem cells using new gene editing technologies that can precisely introduce patient specific mutations into the genome. These models have the potential to differentiate from stem cells to red blood cells in cell culture. I will use these models to conduct a screen using CRISPR technology to cut the genome at specific sites. This will allow us to systematically test what genetic factors help to overcome impaired red blood cell production as seen with SF3B1-mutated bone marrow stem cells. I will also study how key gene pathways that regulate the differentiation of bone marrow stem cells into red blood cells are altered in SF3B1-mutant bone marrow stem cells. These approaches will help us to define how mutations in splicing factors impair blood cell production and identify new targets for drug development.