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c-myc Down Regulation and Precommitment in HL-60 Cells Due to Bromodeoxyuridine¹

Department of Pathology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853

HL-60 human nonlymphocytic leukemia cells undergo terminal differentiation along either the myeloid or monocytic pathway in a process previously shown to involve two sequential steps, early events leading to a precommitment state and late events leading to onset of terminal differentiation. The present report shows that bromodeoxyurdine induces the early events leading to precommitment. In this course bromodeoxyuridine causes the rapid down regulation of the c-myc protooncogene. The course is similar to other common inducers of HL-60 differentiation including retinoic acid, dimethyl sulfoxide, 1,25-dihydroxyvitamin D₃, and sodium butyrate. HL-60 cells which were initially exponentially proliferating were exposed to 10 µM bromodeoxyuridine for 24 h, a period corresponding to one division cycle in these cells. When the cells were subsequently exposed to either retinoic acid or 1,25-dihydroxyvitamin D₃, onset of G_1/0 specific growth arrest and display of the differentiated phenotype occurred within 24 h. This is in contrast to the 48-h exposure needed for onset of terminal differentiation if either inducer is used singly during continuous exposure, as has been reported previously. Thus bromodeoxyuridine consummated the early events, including the rapid down regulation of c-myc message levels, which occur during the first division cycle of the induced cellular metabolic cascade leading to onset of terminal differentiation. The ability of bromodeoxyuridine to drive events in the metabolic cascade leading to onset of terminal differentiation was specific for early events, inasmuch as it was relatively ineffective at driving late events. Down regulation of c-myc was not in itself sufficient to result in subsequent terminal differentiation, since pulse exposure to bromodeoxyuridine followed by culture in inducer free medium resulted in little G_1/0 specific growth arrest or phenotypic differentiation. Continuous exposure to bromodeoxyurdine, in contrast, resulted in significant G_1/0 specific growth arrest but little phenotypic differentiation, indicating that the regulation of cell cycle transit and differentiation are separable.

¹ Supported in part by grants from the USPHS (NIH), American Institute for Cancer Research, Council for Tobacco Research, Cornell Biotechnology Program, and Cornell BRSG.

Received 2/ 2/89. Revised 8/ 1/89. Revised 11/ 6/89. Accepted 11/15/89.

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