Gene controlled negative regulation of DNA synthesis in erythropoietic progenitor cells.

Congenic strains differing by a small segment of Chromosome 9 that bears the Fv-2 locus have provided valuable material for investigating genetic resistance to Friend polycythemia virus (FV). C57BL/6 (B6) (Fv-2rr) mice have been found to differ from B6.S (Fv-2ss) mice not only in their response to this virus but also in the proliferative state of their erythropoietic progenitor cells BFU-E: in B6 mice the majority of BFU-E are normally quiescent, while in B6.S mice approximately 50% are actively synthesizing DNA at any time. We have shown that B6 but not B6.S marrow contains a macromolecule that negatively regulates DNA synthesis specifically of BFU-E in vitro. Evidence is presented that this macromolecule is a physiological negative regulator active in vivo in B6 mice. A new liquid culture system is described in which FV and erythropoietin (epo) act synergistically on Ficoll-Isopaque separated bone marrow cells to give rise after 7 days to large numbers of CFU-E detectable in 2-day plasma cultures with and without epo. Inclusion of concentrated B6 but not B6.S bone marrow supernatant in liquid cultures drastically curtailed the amplification of CFU-E by FV and epo. These studies indicate that both DNA synthesis and the BFU-E stage of differentiation are necessary conditions for initiating the effects of polycythemia-inducing FV. Genetic resistance to FV appears not to reside within the target cells for the virus.