The proto-oncogene c-myc blocks myeloid differentiation independently of
its target gene ornithine decarboxylase
M Selvakumaran, D Liebermann and B Hoffman
Fels Institute for Cancer Research and Molecular Biology, Temple University
School of Medicine, Philadelphia, PA 19140, USA.
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.
Volume 88,
Issue 4,
pp. 1248-1255,
08/15/1996
Copyright © 1996 by The American Society of Hematology
