Terminal myeloid differentiation is uncoupled from cell cycle arrest.

It has been assumed that terminal myeloid differentiation and cell cycle arrest are coupled processes, and that prohibiting cell cycle arrest would block differentiation. Previously we have shown that, using the murine M1 myeloid leukemic cell line, deregulated expression of the proto-oncogene c-myc results in cells that cannot be induced to undergo terminal differentiation and continued to proliferate. It has also been shown that ectopic expression of Egr-1 abrogated the c-Myc block in terminal myeloid differentiation, yet there was no accumulation of cells in the G0/G1 phase of the cell cycle. In this study we conclusively demonstrate that M1Myc/Egr-1 cells terminally differentiate while still actively cycling and synthesizing DNA, concluding that the terminal myeloid differentiation program is uncoupled from growth arrest. How deregulated expression/activation of proto-oncogenes that promote cell cycle progression interferes with differentiation and how differentiation is regulated independently of cell cycle control are discussed, as well as the implications with regard to differentiation therapy.