Louis M. Pelus, PhD
Professor of Microbiology & Immunology
To identify mechanisms of action of stem cell mobilizers that will lead to safer and faster isolation of blood stem cells that can be used to cure leukemia and other cancers; to understand the role of the inhibitor of apoptosis family of proteins in normal and cancer biology.
Dr. Pelus' laboratory is interested in the mechanisms that control blood cell proliferation, differentiation and migration, and how these pathways can be leveraged to define new therapies for leukemia and cancer. The primary focus of the laboratory is to understand the mechanisms that control hematopoiesis, the process by which blood cells are produced, and the disordered regulation of cell proliferation and survival characteristic of cancer cells. These studies are progressing at the molecular, cellular and animal level. In the hematopoietic system, marrow stem cells can be forced to migrate to peripheral blood where they can be collected and used for transplantation, a curative therapy for many cancers. The laboratory has identified GRO beta , a member of a family of peptides called chemokines, which stimulates the migration of stem cells that are able to completely reconstitute hematopoiesis from bone marrow to blood. Chemokine "mobilized" stem cells restore blood formation more rapidly than cells mobilized by hematopoietic growth factors such as G-CSF. The chemokine GRO beta specifically interacts with the CXCR2 chemokine receptor on blood neutrophils releasing matrix metalloproteinases that we believe are responsible for the "release" of cells from bone marrow. Studies are currently underway to determine the differences between GRO beta and G-CSF mobilized stem cells, the intracellular and extracellular events initiated by GRO beta -CXCR2 interaction that leads to migration of stem cells and how this is regulated, and how combination therapy with other cytokines, chemokines and their receptors can define new paradigms for stem cell transplantation. The answer to these questions will benefit patients receiving extensive chemotherapy who require hematopoietic support or who could benefit from curative hematopoietic stem cell transplantation.
Identification of genes in stem cells that are regulated by hematopoietic growth factors and involved in normal cell proliferation and in the "override" of programmed cell death or "apoptosis" characteristic of cancer cells, is another prime area of interest of the laboratory. We have determined that the recently identified inhibitor of apoptosis family member, Survivin, that has been linked to unchecked proliferation in cancer cells, may play an important role in regulating cell cycle entry and cell division in normal hematopoietic stem cells. We are currently defining the intracellular mechanisms whereby Survivin regulates cell cycle, and using retroviral and mouse genetic model approaches to determine the consequences of modulating Survivin expression on long-term hematopoiesis in vivo and its oncogenic potential. We have identified novel intracellular signaling pathways for Survivin, interacting with the p53 family of tumor suppressors, c-Abl and Cdc34 and are characterizing the contribution of these pathways to tumorigenesis.