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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2382-2388
HEMATOPOIESIS
Multipotent hematopoietic cell lines derived from C/EBP ( /)
knockout mice display granulocyte macrophage-colony-stimulating
factor, granulocyte- colony-stimulating factor, and retinoic
acid-induced granulocytic differentiation
Steven J. Collins,
Jon Ulmer,
Louise E. Purton, and
Gretchen Darlington
From the Human Biology Division, Fred Hutchinson Cancer
Research Center, Seattle, WA; and the Department of Pathology and the
Huffington Center on Aging, Baylor College of Medicine, Houston, TX.
The transcription factor C/EBP is an important mediator of
granulocyte differentiation and regulates the expression of multiple granulocyte-specific genes including the
granulocyte-colony-stimulating factor (G-CSF) receptor, neutrophil
elastase, and myeloperoxidase. Indeed C/EBP knockout mice display a
profound block in granulocyte differentiation. To study this block in
granulocytic differentiation in more detail, retroviral vector-mediated
transduction of a dominant-negative retinoic acid receptor was used to
establish hematopoietic growth factor-dependent, lympho-myeloid
progenitor cell lines from the fetal livers of both the
C/EBP knockout animals (C/EBP( /)) and their
heterozygous littermates (C/EBP(+/)). Surprisingly, the
C/EBP(/) cell lines displayed significant spontaneous
granulocytic differentiation, and this differentiation was markedly
enhanced when the cells were stimulated with granulocyte macrophage
(GM)-CSF. This GM-CSF-mediated differentiation was associated with
the up-regulation of G-CSF receptor mRNA, and the combination of GM-CSF
and G-CSF generated more than 95% mature neutrophils in the
C/EBP(/) cultures. The addition of all-trans
retinoic acid also enhanced this granulocytic differentiation of the
cultured C/EBP(/) cells, indicating that the activated retinoic
acid receptors can enhance granulocytic differentiation through a
molecular pathway that is independent of C/EBP. These studies
clearly indicate that terminal granulocytic differentiation associated
with the up-regulation of C/EBP-responsive genes can occur in the
absence of C/EBP, and they indicate the existence of multiple
independent molecular pathways potentially used by primitive
hematopoietic precursors that can lead to the development of mature granulocytes.
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