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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1971-1978
Involvement of the Retinoblastoma Protein in Monocytic and Neutrophilic
Lineage Commitment of Human Bone Marrow Progenitor Cells
Gösta Bergh,
Mats Ehinger,
Inge Olsson,
Sten Eirik W. Jacobsen, and
Urban Gullberg
From the Department of Hematology, and the Stem Cell Laboratory,
Department of Internal Medicine, University of Lund, Lund, Sweden.
The retinoblastoma gene product (pRb) is involved in both cell cycle
regulation and cell differentiation. pRb may have dual functions during
cell differentiation: partly by promoting a cell cycle brake at
G1 and also by interacting with tissue-specific transcription factors. We recently showed that pRb mediates
differentiation of leukemic cell lines involving mechanisms other than
the induction of G1 arrest. In the present study, we
investigated the role of pRb in differentiation of human bone marrow
progenitor cells. Human bone marrow cells were cultured in a
colony-forming unit-granulocyte-macrophage (CFU-GM)
assay. The addition of antisense RB oligonucleotides ( -RB), but not
the addition of sense orientated oligonucleotides (SO) or scrambled
oligonucleotides (SCR), reduced the number of colonies staining for
nonspecific esterase without affecting the clonogenic growth. Monocytic
differentiation of CD34+ cells supported by FLT3-ligand
and interleukin-3 (IL-3) was correlated to high levels of
hypophosphorylated pRb, whereas neutrophilic differentiation, supported
by granulocyte colony-stimulating factor (G-CSF) and stem cell factor
(SCF), was correlated to low levels. The addition of -RB to liquid
cultures of CD34+ cells, supported with FLT3-ligand and
IL-3, inhibited monocytic differentiation. This was judged by
morphology, the expression of CD14, and staining for esterase.
Moreover, the inhibition of monocytic differentiation of
CD34+ cells mediated by -RB, which is capable of
reducing pRb expression, was counterbalanced by an enhanced
neutrophilic differentiation response, as judged by morphology and the
expression of lactoferrin. CD34+ cells incubated with
oligo buffer, -RB, SO, or SCR showed similar growth rates. Taken
together, these data suggest that pRb plays a critical role in the
monocytic and neutrophilic lineage commitment of human bone marrow
progenitors, probably by mechanisms that are not strictly related to
control of cell cycle progression.
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