REGULATION OF MYELOPOIESIS: SUPPRESSOR FACTOR SYNERGISM

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The control of proliferation of hematopoietic stem and progenitor cells in vivo is most likely the end result of the production and action of growth-stimulating and growth-suppressing molecules. We have defined and characterized the influence of purified natural and recombinant molecules such as acidic isoferritins, the interferons gamma, alpha and beta, the E type prostaglandins, and tumor necrosis factor on normal and abnormal hematopoiesis. Of much interest to us, and potentially of great importance and relevance to an understanding of the physiological regulation of hematopoietic cell proliferation in vivo and of abnormalities in this regulation during leukemia and related blood disorders is the recent findings by us and others that certain molecules can synergise with each other in vitro so that the effects noted are much greater than additive. We propose to investigate the phenomenon of synergism between molecules in vitro and in vivo. Our aims are to evaluate further and more precisely the actions and interactions alone and in combination of well-characterized and purified natural or recombinant acidic isoferritins, interferons-gamma and -alpha, prostaglandin E1 or E2 and tumor necrosis factor on the growth in vitro of fresh primary normal human and murine myeloid cells, on cells from patients with leukemia and related disorders, and on established human myeloid leukemia cell lines in vitro. Our goal is to study these molecule-cell interactions using pure molecules and purified populations of target cells, isolated by biophysical and immunological procedures, in the presence and absence of serum. Studies in vitro will include an analysis of the activity of these molecules using colony forming cell assays (CFU-GM, BFU-E, CFU-GEMM, S-cells), the receptor-binding capacity of these molecules, and effects of these molecules on the expression of proto-oncogenes. We also propose to evaluate the separate and combined actions of these molecules in vivo in mice undergoing rebound myelopoiesis, in untreated mice, and in mice infected with the Friend Viruis Complex. We believe that the studies proposed will increase our understanding of the relevance of these molecules and the concept of synergism as it applies to normal and abnormal regulation.