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 FL?vac? 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)

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Pathology B Study Section (PTHB)
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Mount Sinai School of Medicine
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Joesten, M E; Royston, M E; Pogo, B G (1989) Tissue specificity in the expression of Friend erythroleukemic virus sequences in infected mouse tissues. Leuk Res 13:233-9
Lai, A C; Pogo, B G (1989) Attenuated deletion mutants of vaccinia virus lacking the vaccinia growth factor are defective in replication in vivo. Microb Pathog 6:219-26
Pogo, B G; Lai, A C; Holland, J G et al. (1988) Differences in the susceptibility of human blood cell lines to vaccinia virus. Intervirology 29:11-20
Friend, C; Zajac-Kaye, M; Holland, J G et al. (1987) Depletion of sodium butyrate from the culture medium of Friend erythroleukemia cells undergoing differentiation. Cancer Res 47:378-82
Friend, C; Zajac-Kaye, M; Holland, J G et al. (1987) Recent studies on the mechanism of induction of differentiation in murine erythroleukemia cells. Haematologica 72:75
Obom, K M; Popple, S W; Holland, J G et al. (1986) Vaccinia virus DNA sequences in the nucleus of persistently infected Friend erythroleukemia cells. Virus Res 5:221-34
Zajac-Kaye, M; Brown, E; Friend, C (1986) Induction of differentiation in Friend erythroleukemia cells with dimethyl sulfoxide, hexamethylene bisacetamide and sodium butyrate is not accompanied by changes in proviral DNA or its expression. Virus Res 6:45-55
Friend, C; Pogo, B G (1985) The molecular pathology of Friend erythroleukemia virus strains. An overview. Biochim Biophys Acta 780:181-95
Brown, E H; Zajac-Kaye, M; Pogo, B G et al. (1985) Rat cells infected with anemia-inducing Friend leukemia virus contain integrated replication-competent but not defective proviral genomes. Proc Natl Acad Sci U S A 82:5925-9