A washable macromolecule from Fv2rr marrow negatively regulates DNA synthesis in erythropoietic progenitor cells...

The proportion of BFU-E normally engaged in DNA synthesis is low in adult B6 (C57BL/6) mice of genotype Fv2rr (resistant to Friend erythroleukemia virus), as shown by 3H-thymidine or hydroxyurea "cell suicide" experiments in vivo and vitro. When bone marrow cells from these mice were subjected to a single wash in alpha medium, the proportion of BFU-E synthesizing DNA dramatically rose to levels as high as those normally seen among the BFU-E of congenic B6.S mice of genotype Fv2ss (sensitive to Friend erythroleukemia virus). Washing Fv2rr marrow cells did not significantly affect the proportion of CFU-S, CFU-nm (CFU-C) or CFU-E engaged in DNA synthesis. An activity responsible for keeping low the proportion of BFU-E in DNA synthesis was recovered in supernatants of FV2rr (but not FV2ss) bone marrow cells; its effect could be demonstrated on the BFU-E of either Fv2rr of Fv2ss washed bone marrow cells. This activity was nontoxic to the BFU-E, rapidly reversible and effective at, but not far below, the concentrations normally found in adult Fv2rr marrow. It was stable to 56 degrees C for 30 min, was nondialyzable, appeared in the void volume on G-25 Sephadex gel filtration and could be filtered through membranes that permitted passage of particles of less than 100,000 but not less than 50,000 daltons. Thus the Fv2 locus (or a locus closely linked to it) appears to act not in the BFU-E itself, but elsewhere, to control the amount or activity of a macromolecular negative regulator to which the BFU-E population responds by a reduction in the proportion synthesizing DNA. This study reveals the existence of a negative growth control mechanism for early erythropoietic progenitor cells, which is apparently physiological in nature and under strict genetic control.