Hematopoiesis consists of a series of regulated steps involving expansions (cell proliferation) and developmental choices (lineage commitment) that lead to the generation of mature blood cell lineages, including the cellular components of both acquired and innate immunity. Some immune cells complete their development in the bone marrow (e.g., NK cells) whereas others develop in secondary lymphoid tissues such as the thymus (e.g., T and NK-T cells). The goal of this proposal is to further study the role of MEF, a member of the ETS family of transcription factors, in innate immunity and hematopoiesis, based on our findings in MEF-deficient mice that we have generated in our laboratory. These mice exhibit greater numbers of hematopoietic stem cells (HSC), impairment in the development and function of natural killer cells (NK and NK-T cells) and lack of perforin expression. This phenotype resembles the human disease Familial Hemophagocytic Lymphohistiocytosis (NK cell dysfunction and immune deregulation). Insights into how the innate immune system and hematopoietic stem cell maintenance are regulated at a transcriptional level will provide a basis for optimizing therapeutic interventions in hematologic disorders and recovery after stem cell transplantation. Our findings raise important biological questions: What is the role of MEF in the function of natural killer cells and how does this affect the innate immune system? What is the precise role of MEF in stem cell quiescence? What MEF-target genes are involved in such processes? Can overexpression of MEF induce stem cell exhaustion or skew lineage commitment to the lymphoid compartment? Aiming to answer these questions we propose to further define the role of MEF in the innate immune system by studying the functional properties of MEF-deficient mice (Aim 1). We will characterize the role of MEF in stem cell quiescence, cell cycle and self-renewal by studying HSCs from MEF-deficient mice in vitro and in vivo (Aim 2). We will further study how MEF regulates the expression of a key target gene (perforin), define the molecular circuitry of NK cells and hematopoietic stem cells using DNA microarray technology, and evaluate the effect of ectopic expression of MEF on tumorigenesis and hematopoiesis (Aim 3).
