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Differentiation and Retrodifferentiation of Human Myeloid Leukemia Cells Is Associated with Reversible Induction of Cell Cycle-regulatory Genes¹

Laboratory of Clinical Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [R. H., H. G., R. D., S. K., D. K.]; Abteilung Virologie, Deutsches Krebsforschungszentrum, D-6900 Heidelberg, Germany [A. H.]; and Department of Radiation and Cellular Oncology, University of Chicago and Pritzker School of Medicine, Chicago, Illinois 60637 [R. W.]

Treatment of human myeloid leukemia cells (HL-60, U-937, THP-1) with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with differentiation along the monocytic lineage. This induction by TPA is characterized in part by growth arrest and the appearance of differentiated monocytic phenotype. The present studies demonstrate that myeloid leukemia cells exit the cell cycle to G₀-G₁ between 24 and 36 h following TPA treatment. This G₀-G₁ arrest was accompanied by down-regulation of the cell cycle-regulatory genes cdc2, cyclin A, cyclin B, and cdc25. Similar findings were obtained for histones H1 and H4. Cell cycle progression of synchronized U-937 cells revealed low to undetectable mRNA levels for these genes in G₁ and maximal transcription in G₂-M phase. Results obtained from mRNA half-life studies demonstrate that the stability of cdc2, cyclin A, cyclin B, and cdc25 transcripts is similar in control and TPA-treated U-937 cells. Nuclear run-on assays demonstrated down-regulation of histone gene transcription, while there was no signal detectable for the cell cycle-regulatory genes. The present findings also demonstrate that long term culture of TPA-differentiated U-937 cells is associated with a decrease in G₀-G₁-arrested cells and an increase of cells in S and G₂-M after 25 days. This reentry into the cell cycle was accompanied by loss of adherence, down-regulation of markers for the monocytic phenotype, and induction of the cell cycle-regulatory genes. This process of retrodifferentiation was completed after 36 days when patterns of cell cycle-regulatory and histone gene expression were identical to that in untreated U-937 cells.

¹ This work was supported by USPHS Grant CA42802 awarded by the National Cancer Institute, Department of Health and Human Services; by a Burroughs Wellcome Award in Clinical Pharmacology (D. K.); and by a Fellowship from the Deutsche Forschungsgemeinschaft (R. H.).

² To whom requests for reprints should be addressed.

Received 6/24/91. Accepted 1/ 7/92.

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