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The repertoire of glycoproteins expressed on the plasma membrane of hematopoietic cells reflects their state of differentiation and maturation. Many of these "differentiation antigens" were first identified using monoclonal antibodies. The expression of differentiation antigens by subsets of hematopoietic cells has been extensively studied, but the biologic function of the majority of these proteins is undetermined. However, there is growing evidence that many such proteins that demonstrate lineage-specific, developmentally regulated expression have important physiologic roles reflecting various effector cell functions of the particular leukocytes that express them. The p67 antigen, recognized by the CD33 group of monoclonal antibodies, is expressed on progenitors of myeloid cells and by members of the granulocytic lineage capable of proliferation, but not on terminally differentiated granulocytes. The human gene encoding p67 has been isolated in a mouse genetic background by three serial rounds of DNA-mediated gene transfer and fluorescence- activated cell sorting with a CD33 antibody. A unique sequence probe for the human p67 locus was derived from these tertiary mouse cell transformants and used to obtain biologically active genomic clones encoding p67 and to assign this gene to chromosome 19. This probe has also been used to identify a partial complementary DNA (cDNA) clone from an HL-60 cell cDNA library. Further efforts will be focused on obtaining full- length cDNA clones that can be utilized to determine the primary structure of p67 and to determine the organization of the exons and introns of this gene. This will enable future studies to elucidate the control mechanisms that confer specific expression of p67 in immature myeloid cells. Preliminary studies indicate p67 is phosphorylated on tyrosine residues in mouse cell transformants that coexpress the v-fms oncogene, but that p67 does not itself possess intrinsic tryosine kinase activity. The phosphorylation of p67 will be further studied in mouse cell transformants that are coexpressing other activated oncogenes or in response to growth factors whose receptors exhibit tyrosine kinase activity. Thus the reagents developed during the first two years of this award will allow me to determine the primary structure of p67, to investigate its role in cellular proliferation during myelopoieses as a substrate for a tyrosine-specific kinases, and to study the transcriptional regulation of this gene.
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