Elucidating function of disease-related SAMD9L mutations in hematopoiesis - (PLEASE KEEP IN WORD, DO NOT PDF) Germline mutations in SAMD9L are a major cause of inherited bone marrow failure and pediatric myelodysplastic syndrome, frequently associated with poor clinical outcomes. Although these mutations are known to impair hematopoietic stem cell function, the cellular mechanisms linking genetic disruption to disease progression remain incompletely understood. This project aims to define the physiological role of SAMD9L in maintaining normal hematopoiesis and to determine how pathogenic variants compromise this process. Using patient-relevant human induced pluripotent stem cells and genetically engineered mice models, the proposed studies will investigate how dysregulated cellular stress responses, metabolic pathways, and inflammatory signaling contribute to stem cell dysfunction and disease evolution. The work integrates genetic, cellular, and functional approaches to establish mechanistic links between SAMD9L disruption and impaired blood formation. Expected outcomes include identification of key regulatory pathways that influence disease severity and therapeutic response. Successful completion of this project will advance understanding of inherited bone marrow failure syndromes, support the development of targeted intervention strategies, and establish a strong foundation for the investigator’s independent research program in translational hematology.
