Sandra Zinkel, M.D., Ph.D.
2016 Funding Recipient
How necrotic cell death impacts the surrounding normal bone marrow; determining whether inhibiting necrosis can rescue bone marrow failure in mouse models of MDS.
Vanderbilt-Ingram Cancer Center MDS Research Consortium Award
Hematopoiesis—the creation of new blood cells—is a highly dynamic process that requires a careful balance between cell division, differentiation, and cell death. In MDS, this process is disrupted, resulting in a decline in blood production, anemia and sometimes bone marrow failure. The two major modes of programmed cell death, apoptosis and necroptosis, share some molecular characteristics, but markedly diverge in outcome: apoptotic cells implode, whereas necroptotic cells explode, triggering inflammation that can affect blood cell creation. While genetic studies have identified two proteins that activate apoptosis and restrain necroptosis, it remains unclear why some cells die by apoptosis and others by necroptosis remain. Here we identify a protein that acts as a molecular switch in lab mice to determine cell death fate in hematopoiesis. The loss of this protein can lead to unrestrained necroptosis and inflammation leading to eventual bone marrow failure that closely resembles human MDS. Importantly, this process can be halted by treating the mice with Enbrel, providing proof of concept that inhibiting inflammation caused by necroptosis can impact the functioning of key cells in blood production.
Wagner PN, Shi Q, Irvin MW, Fedoriw Y, Lopez CF, Zinkel SS. Bid regulates programmed cell death fate and hematopoietic stem cell function. Submitted to Science Signaling.
Zhou T, Kinney MC, Scott LM, Zinkel SS, Rebel VI. Revisiting the case for genetically engineered mouse models in human MDS research. Blood. 2015, 126: 1057-1068.
Ratliff M, Alter S, McAvoy K, Frasca D., Wright JA, Zinkel SS, Khan W, Blomberg BB, Riley RL. In aged mice, low surrogate light chain promotes pro-B cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of auto-reactive phosphocholine specific B cells. Aging Cell. 2015, 3: 383-390.