Mononuclear phagocytes (M) are important hematopoietic regulatory cells. Our studies indicate that the granulopoietic activity of M invitro are mediated through other auxiliary cells, including endothelial cells (E) and fibroblasts (F), both constituents of the hematopoietic microenvironment. We have described a model in which, M produce monokine (MRA) which stimulates the production and release of CSA by marrow stromal cells. In the past 2year funding period we have determined; 1) that MRA is interleukin1 (IL1), 2) that similar monokines induce the production and release of growth factors for erythroid bursts, megakaryocytic CFU, and pluripotent -CFU (CFUGEMM) by endothelial cells and marrow fibroblasts, and 3) that autonomous granulopoieses in-vitro is a unique characteristic of chronic granulocytic leukemia of the juvenile type (JCGL) and that this pattern of growth results from excessive activity of moncytederived IL1. During this period we have also developed a technique by which gene expression can be studied at various stages of normal human granulopoietic cellular differentiation. We propose to: 1) characterize coordinately expressed IL1 induced genes by stromal cells, 2) identify cofactors for IL-1 production and IL-1 responsiveness, 3) identify the breadth of growth factors induced by IL-1, 4) identify the differentiation stages at which daughters of CFUGM become competent for IL1 gene expression, and 5) characterize molecular defects of IL1 gene expression in children with JCGL. These studies may identify molecular mechanisms by which stromal cells of the marrow interact with moncyte/macrophages to regulate normal and leukemic hematopoiesis.
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