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The proto-oncogene c-myc blocks myeloid differentiation independently of its target gene ornithine decarboxylase

M Selvakumaran, D Liebermann and B Hoffman

Abstract

Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, has been shown to be required for entry into and progression through the cell cycle and to be a transcriptional target of the proto-oncogene, c-myc. We show that ODC transcripts and enzyme activity are down-regulated following induction of myeloid differentiation, using M1 myeloblastic leukemic cells and normal cells from bone marrow (BM), and fail to be suppressed when c-myc expression is deregulated. In M1mycer cells, when endogenous c-myc expression has been suppressed following stimulation by interleukin-6 (IL-60), treatment with estrogen and cycloheximide results in induction of ODC transcripts. These data demonstrate that ODC is a c-myc target gene in M1 cells. It was of interest to determine whether deregulated ODC expression would alter the myeloid differentiation program. To answer this question, M1-ODC cell lines constitutively expressing ODC were established. These cells can undergo terminal differentiation and growth arrest following IL-6 stimulation, exactly like parental M1 cells, demonstrating that deregulated ODC expression is not sufficient to block myeloid differentiation. Another question to be answered was whether ODC expression is necessary for the c-myc-mediated block in differentiation. The use of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, indicates that ODC is not necessary for the c-myc-mediated differentiation block.