Differentiation of murine erythroleukemic (Friend) cells: an in vitro model of erythropoiesis.

Normal erythropoiesis involves differentiation of uncommitted stem cells through committed erythroid precursors into cells specialized for hemoglobin synthesis. Several aspects of this developmental sequence may be studied in murine erythroleukemic cells infected with Friend virus complex. These cells are arrested at the proerythroblast stage, yet capable of continuous growth in vitro. Maturation along an erythroid pathway is induced after treatment with a variety of agents (e.g. dimethylsulfoxide, butyric acid, hemin, ouabain). Following induction, the cells morphologically resemble normoblasts, accumulate globin mRNAs and strain-specific globins, increase heme synthesis and acquire erythrocyte membrane antigens. Cloned populations of erythroleukemic cells mature in a nonhomogeneous fashion upon induction, indicative of a stochastic response in the inductive process. This "probability of differentiation" phenotype is formally analogous to stem cell development in which hematopoietic precursor cells form a constant, dividing population from which cells are continuously maturing. Although the sequence of events involved in triggering differentiation is uncertain, cloning and cell hybridization experiments demonstrate that this phenotype is under rather stable genetic (or epigenetic) control. Recent molecular analysis shows that induced differentiation is accompanied by transcriptional activation of the globin genes rather than posttranscriptional stabilization of the globin RNAs. Further application of cellular, molecular and genetic approaches in this system may help to define specific control mechanisms in erythroid development.