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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2776-2785
HEMATOPOIESIS
CCAAT/enhancer-binding proteins are required for granulopoiesis
independent of their induction of the granulocyte colony-stimulating
factor receptor
Qian-fei Wang and
Alan D. Friedman
From the Division of Pediatric Oncology, Johns Hopkins
University, Baltimore, MD.
Potential redundancy among members of the CCAAT/enhancer-binding
protein (C/EBP) family in myeloid cells is indicated by the ability of
C/EBP to replace C/EBP in vivo, by the expression of granulocyte
colony-stimulating factor receptor (G-CSFR) on C/EBP / cell lines, and by our finding that as with
C/EBP-estrogen receptor (C/EBP-ER), either C/EBP-ER or
C/EBP -ER can induce terminal granulopoiesis in 32D cl3
cells. To assess the consequences of globally inhibiting
C/EBPs, we employed KER, containing a Kruppel-associated box
(KRAB) transrepression domain, the C/EBP DNA-binding
domain, and an ER ligand-binding domain. C/EBPs have a common
DNA-binding consensus, and activation of KER repressed
transactivation by endogenous C/EBPs 50-fold and reduced endogenous
G-CSFR expression. In 32D cl3 cells coexpressing exogenous G-CSFR,
activation of KER prevented and even reversed myeloperoxidase,
lysozyme, lactoferrin, and C/EBP RNA induction by G-CSF. In
contrast, induction of PU.1 and CD11b, a gene regulated by PU.1 but not
by C/EBPs, was unaffected. A KER variant incapable of binding DNA
owing to an altered leucine zipper did not affect 32D cl3
differentiation. Transduction of KER into murine hematopoietic
progenitor cells suppressed the formation of granulocyte colony-forming
units, even in cytokines that enable C/EBP/
progenitors to differentiate into neutrophils. The formation of
macrophage and of granulocyte-macrophage colony-forming units were also
inhibited, but erythroid burst-forming units grew normally. Thus, in
32D cl3 cells and perhaps normal progenitors, C/EBPs are required for
granulopoiesis beyond their ability to induce receptors for G-CSF and
other cytokines. One requisite activity may be activation of the
C/EBP gene by C/EBP, as either C/EBP-ER or C/EBP-ER rapidly
elevated C/EBP RNA in 32D cl3 cells in the presence of cycloheximide
but not actinomycin D.
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