THE PROTOONCOGENE C-MYC BLOCKS MYELOID DIFFERENTIATION INDEPENDENTLY OF ITS TARGET GENE ORNITHINE DECARBOXYLASE

Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine bio synthesis, has been shown to be required for entry into and progressio n through the cell cycle and to be a transcriptional target of the pro to-oncogene, c-myc. We show that ODC transcripts and enzyme activity a re 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 M 1mycer cells, when endogenous c-myc expression has been suppressed fol lowing stimulation by interleukin-l (IL-60), treatment with estrogen a nd cycloheximide results in induction of ODC transcripts. These data d emonstrate that ODC is a c-myc target gene in M1 cells. It was of inte rest to determine whether deregulated ODC expression would alter the m yeloid differentiation program. To answer this question, M1-ODC cell l ines constitutively expressing ODC were established, These cells can u ndergo terminal differentiation and growth arrest following IL-6 stimu lation, exactly like parental M1 cells, demonstrating that deregulated ODC expression is not sufficient to block myeloid differentiation, An other question to be answered was whether ODC expression is necessary for the c-myc-mediated block in differentiation. The use of alpha-difl uoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme ac tivity, indicates that ODC is not necessary for the c-myc-mediated dif ferentiation block. (C) 1996 by The American Society of Hematology.