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New Insights Into the Negative Regulation of Hematopoiesis by
Chemokine Platelet Factor 4 and Related Peptides
Laurence Lecomte-Raclet,
Mònica Alemany,
Anabelle
Sequeira-Le Grand,
Jean Amiral,
Gérard Quentin,
Anne Marie Vissac,
Jacques P. Caen, and
Zhong Chao Han
From the Institut des Vaisseaux et du Sang, Hôpital
Lariboisière, Paris, France; and Serbio Research Laboratories,
Gennevilliers, France; and the Institute of Hematology, Chinese Academy
of Sciences, Tianjin, China.
Platelet factor 4 (PF4) has been recognized as an inhibitor of
myeloid progenitors. However, the mechanism of action of this chemokine
remains poorly understood. The present study was designed to determine
its structure/function relationship. A series of peptides overlapping
the C-terminal and central regions of PF4 were analyzed in vitro for
their action on murine hematopoietic progenitor growth to assess the
minimal sequence length required for activity. The peptides p17-58 and
p34-58 possessed an increased hematopoietic inhibitory activity when
compared with PF4, whereas the shorter peptides p47-58 and p47-70 were
equivalent to the native molecule and the peptide p58-70 was inactive.
The PF4 functional motif DLQ located in 54-56 was required for the
activity of these peptides. The peptide p34-58 impaired to a similar
extent the growth of colony-forming unit-megakaryocyte
(CFU-MK) as well as burst-forming unit-erythroid
(BFU-E) and colony-forming unit-granulocyte-macrophage (CFU-GM), whereas PF4 was more active on CFU-MK. In the experiments using purified murine CD34+ marrow cells, statistically
significant inhibition induced by p34-58 was shown at concentrations of
2.2 nmol/L or greater for progenitors of the three lineages, whereas
that induced by PF4 was seen at 130 nmol/L for CFU-MK and 650 nmol/L
for CFU-GM and BFU-E, indicating that the p34-58 acts directly on
hematopoietic progenitors and its activity is approximately 60- to
300-fold higher than PF4. The p34-58, unlike PF4, lacked affinity for
heparin and its inhibitory activity could not be abrogated by the
addition of heparin. In addition, an antibody recognizing p34-58
neutralized the activity of p34-58 but not whole PF4 molecule. These
results demonstrate that PF4 contains a functional domain in its
central region, which is independent of the heparin binding properties, and provide evidence for a model of heparin-dependent and independent pathways of PF4 in inhibiting hematopoiesis.
Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 2772-2780
© 1998 by The American Society of Hematology.
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