Regulation of Programmed Necrosis and Bone Marrow Failure
Abstract
Blood cell production is a highly dynamic process, designed to respond to stresses such as infection or bleeding over the entire lifespan of a person or animal. During normal conditions, there is a careful balance between blood cells made and blood cells removed due to aging or damage. A highly regulated process called programmed cell death removes cells, and bone marrow failure occurs when more cells are removed than can be replaced. There are two major pathways of programmed cell death: apoptosis and necrosis. Simply described, apoptotic cells implode in an immune silent process, and necrotic cells explode, activating an inflammatory response. In bone marrow failure disorders, necrotic death of bone marrow cells increases normal bone marrow damage by amplifying the pathological inflammatory response. Recent discoveries have demonstrated that necrosis, long thought to be unregulated, is actually highly regulated by Rip kinases. Understanding how necrosis is controlled and identifying small molecules that inhibit Rip kinases is an area of intense research pursuit, and a number of agents have become available and are in development that target Rip kinases. We have discovered that the bone marrow cell death in patients with myelodysplastic syndromes (MDS) is caused by increased necrosis signaling through Rip kinases. In addition, we have demonstrated increased necrosis signaling in mouse models harboring genetic mutations found in MDS, suggesting that these MDS mutations may result in bone marrow necrosis. MDS has been shown to be a clonal disorder -- a small number of cells harboring genetic alterations are able to expand and impair normal bone marrow function. One of the paradoxes of MDS is that these abnormal cells can outcompete normal bone marrow, but ultimately their expansion causes bone marrow failure. We hypothesize that the increased necrotic cell death in MDS bone marrow initiates a feed-forward inflammatory process that kills normal bone marrow and that targeting this programmed necrotic cell death could be used for therapeutic benefit. This proposal is focused on (1) determining how necrotic cell death impacts the surrounding normal bone marrow and (2) determining whether inhibiting necrosis can rescue bone marrow failure in mouse models of MDS. We have developed and acquired a number of mouse models to test how increased necrosis impacts bone marrow failure. We have constructed a novel mouse model that is genetically engineered to undergo unrestrained necroptosis in the bone marrow. These mice manifest all of the major abnormalities seen in human MDS: (1) low blood counts, (2) death from bone marrow failure, (3) a small percentage of mice that evolve into leukemia, (4) abnormal blood cells (dysplasia). In addition, we have acquired three mouse models with genetic mutations found in MDS as a collaboration with Dr. Omar Abdel-Wahab (Asxl1-/-, Tet2-/-, and Asxl1-/-Tet2-/- mice) and have shown that the bone marrow from these mice displays increased necrosis signaling. We will use bone marrow from these mice mixed with wild-type (normal) bone marrow to perform bone marrow transplants in mice with the goal of understanding how necrotic bone marrow kills wild-type bone marrow. In addition, we will treat these mice with inhibitors of necrosis (necrostatins, Rip1 kinase inhibitors) to determine whether inhibiting necrosis can delay or inhibit bone marrow failure. We acknowledge that this strategy is a high-risk strategy, as it is possible that inhibiting necrosis may increase the chance of transformation to leukemia. However, our preliminary data indicate that the feed-forward inflammation caused by necrosis kills normal bone marrow. We hypothesize that interrupting this inflammatory process will preserve normal bone marrow function and inhibit growth of the abnormal MDS clone. Furthermore, by preserving normal bone marrow function, we will prevent increased proliferation of hematopoietic stem a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610057
Entities
People
- Sandra S. Zinkel
Organizations
- United States Army
- Vanderbilt University