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Changes in c-myc, c-fms, and N-ras Proto-oncogene Expression Associated with Retinoic Acid-induced Monocytic Differentiation of Human Leukemia HL60/MRI Cells

Laboratory of Biological Chemistry, Division of Cancer Treatment, Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

The human promyelocytic leukemia cell line HL60 differentiates to granulocytic cells when treated with retinoic acid (RA). In contrast, HL60/MRI, a cell line established from a transplantable HL60 tumor in nude mice, differentiates to monocytoid cells in response to RA (M. Imaizumi, J. Uozumi, and T. R. Breitman, Cancer Res., 47: 1434–1440, 1987). Because alterations of proto-oncogene expression may be closely related to the difference in response of HL60/MRI to RA we studied the expression of the proto-oncogenes myc, fms, and N-ras of HL60/MRI in comparison to HL60. Compared to HL60, the proto-oncogene myc of HL60/MRI is amplified about twofold less in genomic DNA and is expressed about twofold less at the transcriptional level. Even though two subclones of HL60/MRI, 28B.4 and 5B, have about the same steady-state levels of c-myc mRNA before treatment with RA, 28B.4 has a more rapid decrease of c-myc mRNA after treatment with RA. Based on two differentiation markers, nitro blue tetrazolium reduction and the OKM-5 monocyte-specific surface antigen, 28B.4 exhibits a greater response to RA than does 5B. c-fms mRNA is not detected in uninduced HL60/MRI and HL60 but is expressed during RA-induced differentiation of HL60/MRI to monocytes/macrophages and HL60 to granulocytes. The expression of N-ras mRNA of 5B decreases about twofold during the first 12 h of exposure to RA and is then relatively constant for another 36 h.

¹ Present address: Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980, Japan.

² To whom requests for reprints should be addressed, at Laboratory of Biological Chemistry, Building 37, Room 5D02, National Cancer Institute, Bethesda, MD 20892.

Received 3/10/88. Revised 8/ 1/88. Accepted 8/29/88.