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

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 downregulated 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-l (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. (C) 1996 by The American Society of Hematology.