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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1174-1182
HEMATOPOIESIS
Requirement for mitogen-activated protein kinase activation in
the response of embryonic stem cell-derived hematopoietic cells to
thrombopoietin in vitro
Marie-Dominique Filippi,
Françoise Porteu,
Françoise Le Pesteur,
Valérie Schiavon,
Gaël A. Millot,
William Vainchenker,
Frédéric J. de Sauvage,
Anne Dubart Kupperschmitt, and
Francoise Sainteny
From the Institut National de la Santé et de la
Recherche Médicale U362, Institut Gustave Roussy, Villejuif,
France; the Institut National de la Santé et de la Recherche
Médicale U363, Institut Cochin de Génétique
Moléculaire, Hôpital Cochin, Paris, France; and the
Department of Molecular Oncology, Genentech, San Francisco, CA.
Enforced expression of c-mpl in embryonic stem (ES)
cells inactivated for this gene results in protein expression
in all the ES cell progeny, producing cells that do not belong to the
megakaryocytic lineage and are responsive to PEG-rhuMGDF, a
truncated form of human thrombopoietin (TPO) conjugated to polyethylene
glycol. These include a primitive cell called BL-CFC, thought to
represent the equivalent of the hemangioblast, and all myeloid
progenitor cells. In this model, PEG-rhuMGDF was able to potentiate the
stimulating effects of other growth factors, including vascular
endothelial growth factor, on BL-CFC and a combination of cytokines on
the growth of granulocyte macrophage-colony-forming units. The
importance of the C-terminal domain of Mpl and of mitogen-activated
protein kinase (MAPK) activation in TPO-dependent megakaryocytic
differentiation has been well studied in vitro. Here, the role of this
domain and the involvement of MAPK in upstream and nonmegakaryocytic cells are examined by using 2 truncated mutants of Mpl ( 34, deletion of residues 71 to 121 in the C-terminal domain; and 3, deletion of
residues 71-94) and specific inhibitors of the MAPK pathway. The 2 deleted regions support different functions, mediated by different
signals. Residues 71 to 121 were required for PEG-rhuMGDF-dependent growth of BL-CFC, for megakaryocytic and other myeloid progenitors, and
for megakaryocyte polyploidization. These responses were mediated by
the ERK1-ERK2 MAPK pathway. In contrast, the only function of the
sequence comprising residues 71 to 94 was to mediate the synergistic
effects of PEG-rhuMGDF with other hematopoietic growth factors. This
function is not mediated by MAPK activation.
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