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Spontaneous Commitment of Murine Erythroleukemic Cells to Terminal Differentiation

Department of Hematology, Hadassah University Hospital, Jerusalem, Israel

Differentiation in murine erythroleukemic cells is arrested at the proerythroblast stage. A small fraction of the population, however, undergoes spontaneous differentiation. This spontaneous differentiation was examined at the individual cell level in relation to cell multiplication, commitment, and maturation. The results indicate that murine erythroleukemic cells destined to undergo spontaneous differentiation first undergo commitment, an irreversible process characterized by cells becoming (a) capable of producing hemoglobin coupled with (b) a loss of their ability to undergo more than six subsequent cell divisions. Commitment is followed by a maturation process which includes the accumulation of erythroid specific markers, e.g., hemoglobin. With respect to commitment, spontaneous differentiation resembles the differentiation produced by most inducers but differs from that evoked by hemin. Serum hemin may therefore be exempt from implication in the spontaneous process. 12-O-Tetradecanoylphorbol-13-acetate, which is known to inhibit murine erythroleukemic cell differentiation, was found to exert its inhibitory effect on both the commitment and maturation steps of spontaneous differentiation. The results further indicate that cells become committed mainly during the logarithmic rather than the stationary phase of the growth cycle. Once committed, however, the cells mature during both the logarithmic and stationary phases. When logarithmic growth was maintained continuously, the rate of the spontaneous differentiation increased (20- to 100-fold) due to the higher probability of cell commitment. A steady state culture was obtained in which the rates of cell multiplication, initiation of commitment, and maturation remained constant.

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Received 2/ 8/82. Accepted 6/ 8/83.