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Commitment to Erythroid Differentiation in Mouse Erythroleukemia Cells Is Controlled by Alterations in Topoisomerase II Phosphorylation¹

University of Illinois at Chicago, College of Medicine, Department of Surgical Oncology, Chicago, Illinois 60612 [A. I. C., N., N. K.]; Loyola University Medical School, Department of Radiotherapy, Maywood, Illinois 60153 [A. T. M. V.]; and IARC, Unit of Multistage Carcinogenesis, Lyon 69372 Cedex 08, France [H. Y.]

To explore the program of cell differentiation in Friend murine erythroleukemia (MEL) cells, we used three clonal variants: phorbol 12-myristate 13-acetate (PMA)-hypersensitive TS-19-101, PMA-resistant TR19-9, and hexamethylene bis-acetamide (HMBA)- and PMA-resistant DS19/R1. After treating TS19-101 cells with HMBA, topoisomerase II (topo II) enzymatic activity was dramatically reduced, and cells became terminally differentiated. The initial reduction in activity was soon followed by reduced topo II phosphorylation, but only later did the protein level drop significantly. PMA, which completely blocked HMBA-induced differentiation in TS19-101 cells, increased the phosphorylation of topo II and restored the enzymatic activity to its original levels. Reduced topo II activity and phosphorylation were also evident in HMBA-treated TR19-9 cells. PMA failed to restore topo II activity and phosphorylation to their original levels in TR19-9 cells. Predictably, the topo II activity and phosphorylation of DS19/R1 cells showed little change in response to HMBA or PMA treatment. Structural changes in chromatin became evident in sensitive cells 24 h after HMBA treatment, suggesting that alterations in topo II phosphorylation may control cell differentiation by altering nuclear architecture.

¹ This work was supported by NIH National Cancer Institute Grants CA-62184 and CA-55840.

² To whom requests for reprints should be addressed, at Department of Surgical Oncology (M/C 820), 840 South Wood Street, Chicago, IL 60612. Phone: (312) 413-1155; Fax: (312) 996-9365; E-mail: andreasc@uic.edu.

Received 4/30/96. Accepted 7/15/96.

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