CONTROL MECHANISMS OF DIFFERENTIATION AND MALIGNANCY

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Our studies are directed primarily toward elucidating the mechanism of action of compounds which modulate gene action in murine virus-induced erythroleukemia cells and the lines derived from them. We continue to investigate the mechanism of action of biological response modifiers, since it is not understood how DMSO or a variety of unrelated compounds act to trigger the program of erythroid differentiation. Studies on Nabutyrate-treated murine virus-induced erythroleukemia cells revealed that they do not undergo the morphological alteration that usually accompanies induction of differentiation. After 4 days of treatment with DMSO or HMBA, two potent inducers, most of the cells are committed to the erythroid pathway and proceed to terminal differentiation in the absence of the inducer whereas cells treated with Nabutyrate "dedifferentiate" within 48 hrs after the inducer is removed from the medium. 14C-Nabutyrate uptake studies suggest it may act through mechanisms different from those of DMSO and HMBA. The patterns of proteins (other than histones) with affinity for ss or ds DNA in undifferentiated and differentiated erythroleukemia cells are also being compared. After induction with DMSO, a new nuclear protein appears whereas another DNA-binding protein disappears. Studies on the effect of other inducers and the binding of specific DNAs are underway. In our FLvac cells, which are dually infected with vaccinia virus, the response to induction, the pattern of retroviral integration and the expression of gp70, gp52, and gp30 do not appear to be altered. Vaccinia DNA sequences, found in the nucleus of cells synthesizing virus, are not integrated. We have developed human hematopoietic cell lines persistently infected with vaccinia are using them to study the effect of induced differentiation. (M)