?s abstract) The ETS family of transcription factors play key roles in the regulation of hematopoiesis. ETS factors regulate critical events in hematopoietic development as demonstrated by the profound defects observed in mice deficient in these genes. The aberrant expression of ETS family members has been linked to the pathogenesis of several types of human and murine leukemia as well as other malignancies. MEF (myeloid elf-1 like factor) is a member of the ETS family cloned from a human megakaryocytic leukemia cell line (CMK). MEF activates transcription of genes important in hematopoiesis including the cytokines GM-CSF and IL-3. MEF interacts with the transcription factor AML1, and the AML1/ETO fusion protein, the product of the (8;21) translocation in acute myelogenous leukemia, and cooperates with AML1 in the regulation of the IL-3 promoter. To evaluate the role that MEF plays in hematopoietic cell development and function, the regulatory pathways central to MEF function will be defined. 1) A tetracycline-inducible MEF expression hematopoietic cell model will be used for differential gene expression analysis with DNA microarrays to identify target genes, which will be validated, and their regulation studied. 2) The functional domains of MEF that regulate the interaction with AML1B and cyclin A will be characterized and their role in regulating target gene expression will be studied. 3) the phenotype of MEF deficient mice generated by homologous recombination will be characterized to define the role of MEF in the development of the hematopoietic, as well as other, systems. Gross, microscopic, and cell-type specific functional abnormalities will be assessed with particular attention to the hematopoietic system. This work will contribute to defining the relationship between mechanisms of cellular development and differentiation and the establishment of disease. Work in the area of hematopathology where diagnostic skills will be developed. Experience in the analysis of mouse models, the use of emerging microarray technology to study and diagnose disease, and clinical diagnostic development will lead to an independent career as a physician scientist.
