A Novel Model of Poikiloderma with Neutropenia Identifies New Targets of USB1 During Hematopoieitic Failure
Abstract
Poikiloderma with Neutropenia (PN) is a rare bone marrow failure disease, with patients coming to clinical attention during infancy and early childhood. In addition to severely compromised blood development, these patients also present with severe skin lesions, atrophy, and an increase chance of infections. All of the patients diagnosed with PN have genetic mutations (alterations) in a gene called USB1. This gene provides instructions for making a protein that functions as an RNA exonuclease. RNA exonucleases are a group of proteins which are responsible for “chewing” building blocks of RNA (called nucleotides), one at a time from molecules of RNA (RNA is a “chemical cousin” of DNA). This process of chewing nucleotides can protect some RNA molecules from premature destruction. This is a crucial event for cells and tissues in our bodies, as RNA molecules control all aspects of the functioning of a cell. If RNA is damaged, absent, or unstable, cells will not function properly, leading to human disease. We now understand that the correct function of our tissues and organs is extremely dependent on adult stem cells. When these cells divide they are able to maintain their state, a process termed self-renewal, and also generate specialized cells that perform a specific function in any given tissue, through a process called differentiation. For instance, hematopoietic stem cells are blood-forming stem cells that are found in the bone marrow and therefore, must be able to grow during the entire life of an individual, giving rise to 1 trillion blood cells every day. Since RNA plays a role in the functioning of stem cells, the consequences of not having efficient RNA maintenance mechanisms could be catastrophic for the circulatory system, since hematopoietic stem cells will be unable to maintain their self-renewal and differentiation capacity to generate blood cells. In fact, several mutations that affect different aspects of RNA biology, including mutations in USB1, have been identified in patients suffering from different but severe forms of bone marrow failure, including poikiloderma with neutropenia. Research regarding PN has been hampered by a lack of adequate models, as existing research models do not properly mimic the disease progression observed in humans. To circumvent this issue, we have engineered human pluripotent stem cells harboring clinically relevant mutations in USB1 that are found in bone marrow failure patients, and developed the technology to differentiate these stem cells in a controlled, quantitative fashion, to become any particular blood cell type present in the circulatory system. This allows us, for the first time, to not only reproduce the clinical effect of this disease in a tissue culture dish, but to find alternatives to correct their molecular defect and restore blood formation. This novel platform represents the most robust system to understand the underlying mechanism behind bone marrow failure in human samples. In this proposal we will use our novel system to study different strategies to rescue blood production in cells with mutations in USB1. Successful completion of the aims of this proposal will positively impact the clinical management of patients afflicted with bone marrow failure. Our proposal is built from strong preliminary data and utilizes novel technologies to directly interrogate molecular mechanisms to restore stem cell function, and therefore blood production, in patients suffering from bone marrow failure. These studies are perfectly aligned with the goals of the Bone Marrow Failure Research Program. Currently, there is no cure for bone marrow failure arising from mutations in USB1. Our proposal benefits from the synergism of the Batista and Parker laboratories, and our combined expertise in bone marrow failure, stem cell biology, and RNA biology puts us in an optimal position to perform the proposed studies. Our proposal represents a novel approach to bone marrow failur
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110447
Entities
People
- Luis Batista
Organizations
- United States Army
- Washington University in St. Louis