Molecular and cellular mechanisms of leukemic hemopoietic cell differentiation: an analysis of the Friend system.

Murine erythroleukemia (MEL or Friend) cells grown in culture and induced to differentiate into cells resembling orthochromatic normoblasts provide a suitable system for uncovering molecular and cellular mechanisms of hemopoiesis and for understanding globin gene regulation. Inducer-treated cells undergo an irreversible commitment to maturation and accumulate large amounts of hemoglobin. Clonal analysis of commitment of individual cells combined with biochemical measurements has revealed that MEL cell differentiation is a highly coordinated set of events (program) leading to the differentiated erythroid state. The developmental program of MEL cells consists of early and late processes. The early events appear to be membrane-mediated processes which operate independently of each other and lead to commitment to terminal maturation and hemoglobin synthesis. Inducer-treated cells express an ability to remember ("memory response") previous exposure to inducer and to continue their differentiation after discontinuous exposure to inducer; expression of "memory response" occurs early in differentiation and affects both the initiation of commitment and accumulation of globin mRNA in a similar manner in inducer-treated cells. Commitment to maturation appears to be the central process responsible for determining the pattern of gene expression, limitation of proliferative activity and nuclear condensation. Commitment, however, can occur independently of hemoglobin synthesis. Although initiation of commitment is associated with early membrane-mediated events (e.g., ion-transport), maintenance and completion of maturation erythroid state is a result of a number of cellular processes. These processes are discussed in relation to the molecular and cellular mechanisms of initiation and completion of MEL cell differentiation. The role of the MEL system as a model for studying mouse and human globin gene regulation is presented.