Grant: Project Grant

Our blood is sustained by the daily production of hundreds of billions of cells in our bone marrow in the process known as hematopoiesis. This process requires precise regulation of gene expression within the hematopoietic stem and progenitor cells. Its dysregulation results in devastating disorders, such as inherited bone marrow failures, anemias, immunodeficiencies, and blood cancers. MYSM1 is a DNA binding protein and a regulator of gene expression, and we were among the first to demonstrate its critical role in hematopoiesis in murine models. We established that MYSM1 acts in hematopoietic stem cells to maintain the expression of genes that encode the structural components of the ribosomes, essential to sustain protein synthesis and cellular function. Recently, we and others further reported that MYSM1 mutations result in an inherited bone marrow failure in human, highlighting the biomedical importance of understanding MYSM1 functions in hematopoiesis. Building on these recent advances, the current research program brings together a team of scientists with a unique combined expertise in hematopoietic stem cells and blood cell production, the regulation of gene expression, and mathematical modeling of hematopoiesis. The research program will: (1) analyze the molecular mechanisms through which MYSM1 regulates gene expression in hematopoietic stem and progenitor cells, and (2) apply comprehensive cellular analyses and mathematical modeling of hematopoiesis to dissect the mechanisms that drive the hematopoietic failure in MYSM1-deficiency. These studies advance the understanding of MYSM1 as a specialized regulator of gene expression in hematopoiesis, and of the cellular mechanisms leading to hematopoietic failure with the loss of MYSM1 function. This program will offer novel insights into bone marrow failures and other hematologic disorders, and in the long-term may suggest new strategies for disease management and treatment.