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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2262-2268
NEOPLASIA
Maintenance of retinoic acid receptor alpha pools by granulocyte
colony-stimulating factor and lithium chloride in
all-trans retinoic acid-treated WEHI-3B
leukemia cells: relevance to the synergistic induction of terminal
differentiation
Rick A. Finch,
Jianming Li,
T-C. Chou, and
Alan C. Sartorelli
From the Department of Pharmacology, Yale
University School of Medicine, New Haven, CT; and Memorial
Sloan-Kettering Cancer Center, New York, NY.
Previous studies have demonstrated that combinations of
all-trans retinoic acid (ATRA) with either
granulocyte-colony stimulating factor (G-CSF) or lithium chloride
(LiCl) produced synergistic terminal differentiation of WEHI-3B
myelomonocytic leukemia (D+) cells. It was found that
steady-state retinoic acid receptor alpha (RAR ) protein levels were
markedly reduced in these cells after exposure to ATRA. Because the
presence of receptors for a hormone ligand is required for its action,
differentiation therapy with ATRA may be self-limiting. The combination
of G-CSF with ATRA significantly attenuated the loss of RAR protein,
and synergistic terminal differentiation occurred. LiCl was more
effective than G-CSF in preserving RAR pools and synergized with
ATRA more strongly than G-CSF. These findings suggested that the
prevention of RAR protein loss by G-CSF or LiCl in ATRA-treated
cells functioned to extend the differentiation response to the retinoid
and was responsible, at least in part, for the observed synergism.
D+ cells transfected with an expression plasmid containing
RAR cDNA had a 6- to 8-fold increase in steady-state RAR mRNA
compared with vector-transfected cells and showed a 2- to 3-fold
increase in RAR protein. ATRA caused a reduction, but not a complete
loss, of RAR protein in these transfectants, which were considerably more responsive than parental D+ cells to ATRA as a single
agent, supporting the concept that the protection of RAR pools
results in a heightened differentiation response to ATRA.
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