Induced differentiation of murine erythroleukemia cells: cellular and molecular mechanisms.

Study of inducer-mediated differentiation of murine erythroleukemia cells provides insights into the cellular and molecular mechanisms implicated in cell differentiation. The loss of proliferative capacity is revealed to be a complex multistep process during which the cells progress through a series of stages, including a precommitment "initiation" stage, a stage suggestive of the accumulation of commitment-related factors, and, finally, a stage of expression of the characteristics of the differentiated state. Cell cycle arrest in G1 phase of the cell cycle may, in part at least, be related to down-regulation of protein p53 synthesis. Expression of induced differentiation is accompanied by an acceleration of transcription at the globin loci, and possibly by posttranscriptional modulation of globin mRNA accumulation, as well. Cells at the stage of erythroid cell development represented by the transformed, differentiation-arrested MELC, have acquired a unique DNA structure and chromatin configuration around the globin genes which distinguish them from other, nonerythroid cells; additional complex changes in chromatin configuration accompany, and probably precede, inducer-mediated acceleration of globin gene transcription during terminal differentiation. Passage through G1 and early S phase of the cell cycle, in the presence of inducer, is critical for subsequent globin gene expression and may be important in establishing the chromatin reconfiguration required for gene expression.