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Heterogeneity of Murine Erythroleukemia Cells with Respect to Tumor Promoter-mediated Inhibition of Cell Differentiation¹

Cancer Center/Institute of Cancer Research [E. F., H. Y., I. B. W., R. A. R., P. A. M.], and Departments of Medicine [I. B. W., R. A. R., P. A. M.] and of Human Genetics and Development [R. A. R., P. A. M.], College of Physicians and Surgeons, Columbia University, New York, New York 10032

Spontaneous and induced differentiation of murine erythroleukemia cells (strain 745A DS19) is reversibly inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent promoter of mouse skin carcinogenesis, and by other tumor-promoting macrocyclic plant diterpenes, but it is not by nonpromoting diterpenes. Twelve clones randomly isolated from this strain vary in their response to TPA. All clones are induced to differentiate by several compounds, the most potent of which is hexamethylene bisacetamide. In six clones TPA (100 ng/ml) caused > 90% inhibiion of differentiation, as measured by the appearance of benzidine-reactive cells. In two clones cell differentiation was not inhibited by TPA even at concentrations as high as 1 µg/ml. In four clones, differentiation was only partially inhibited (16 to 47%) by TPA. Clones resistant to TPA inhibition of differentiation were also resistant to structurally related tumor-promoting agents. The isolation of variant cell lines, sensitive and resistant to TPA, provides a tool for elucidating the mechanism of tumor promoter-mediated inhibition of cell differentiation.

¹ These studies were supported in part by grants and contracts from the National Cancer Institute (CA-13696, CA-18314, CA-21111, NO1-CP-1008, and NO1-CP-23234), the National Science Foundation (PCM-75-08696), and the American Cancer Society (CH-68).

² Fellow of The Schultz Foundation.

³ To whom requests for reprints should be addressed.

Received 6/22/78. Accepted 8/ 7/78.