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Distinct roles of U2AF1 mutations in MDS pathogenesis (2021)

Distinct roles of U2AF1 mutations in myelodysplastic syndrome pathogenesis (2021)

Research Interests for Patients

As a physician-scientist I am interested in understanding the genetic and molecular basis of splicing factor gene mutations in clonal hematopoiesis and myeloid malignancies, such as myelodysplastic syndromes (MDS). My postdoctoral work demonstrated that mutations in the U2AF1 splicing factor gene provide an ideal model for these studies as they occur at one of two hotspot codons (S34 and Q157) in separate zinc finger domains, and each of these mutations are associated with different clinical features, outcomes, alternative splicing, and co-occurring gene mutations in MDS patients. Complimentary experiments using U2af1(S34F/+) and U2af1(Q157R/+) small animal models support these observations and have also revealed differential activation of several key signaling pathways. The goal of our lab's research program is focused on answering the following questions: (1) Why are splicing factor mutations highly enriched in clonal myeloid malignancies (e.g., MDS) compared to other types of cancer? (2) What are the individual and shared mechanisms by which different splicing factor mutations induce MDS? (3) What are the dynamics facilitating acquisition of additional mutations in the context of splicing factor mutant disease?