1 Children's Place
St. Louis, MO 63110
06/21/2011

Hematopoietic stem cells (HSCs) are responsible for maintaining the supply of blood cells throughout the life of an individual. Two fundamental properties of stem cells are self-renewal, or the ability to make more stem cells, and quiescence, or the maintenance of a low metabolic state. These essential stem cell properties are regulated by cues from the environment in which the HSCs reside, which consists of specialized "niches" in the bone marrow. The maintenance of these properties is crucial, as dysregulated HSC function can lead to serious blood disorders, including bone marrow failure and leukemia.

Granulocyte-colony stimulating factor (G-CSF) is a naturally occurring cytokine and is the most commonly used drug to prepare stem cells for harvesting for bone marrow transplantation. lt is also widely used clinically to treat patients with low neutrophil (a type of white blood cell) counts. Data from our lab and others has shown that G-CSF treatment is associated with changes in the bone marrow, affecting cells that make up the HSC niche. Given that these cells are important to the maintenance of HSC function, we asked whether G-CSF affected the properties of HSCs. Indeed, when mice are treated with G-CSF, their HSCs display impaired function. Specifically, they are less able to repopulate a transplanted recipient mouse, and demonstrate an impaired capacity for self~renewal. We have also shown that G-CSF alters the cell cycle status of HSCs, ultimately rendering them more quiescent than normal untreated cells.

ln an effort to understand the mechanism by which G-CSF alters HSC function, we have looked for genes that are differentially expressed in HSCs following G-CSF treatment. One such gene is Kruppel like factor 7 (KLF7), a member of a family of transcription factors involved in regulating a wide variety of cellular processes, including cell growth and differentiation. Current experiments are aimed at understanding the role of KLF7 in regulating HSC function. Specifically, we are looking at the effects of over-expressing KLF7, as well as loss of KLF7, on the ability of HSCs to engraft transplanted mice, proliferate, and selfrenew. We are also addressing whether the negative effects of G-CSF on HSC function are mediated by KLF7.

Outcomes include a better understanding of the role of KLF7 in regulating HSC function, which will help us to better understand the regulation of both normal and leukemic stem cells. Further, we expect that these studies will help to elucidate the mechanism by which G-CSF alters stem cell function, which is of critical importance to the field of pediatric hematology/oncology for multiple reasons: 1. G-CSF is widely used to harvest stem cells for bone marrow transplants in individuals with both cancer and non-cancerous conditions; 2. The factors that are important for maintaining normal stem cell function are not entirely clear, and 3. Leukemic cells and other types of cancer cells that metastasize to the bone marrow are thought to behave in some ways like normal stem cells and perhaps even share the same niche, suggesting that we can apply what we learn about the effects of G-CSF on normal HSCs to cancer therapy and use this agent to help fight cancer cells in the bone marrow.