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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1601-1613
Megakaryocyte Growth and Development Factor-Induced Proliferation
and Differentiation Are Regulated by the Mitogen-Activated Protein
Kinase Pathway in Primitive Cord Blood Hematopoietic Progenitors
Serge Fichelson,
Jean-Marc Freyssinier,
Françoise Picard,
Michaela Fontenay-Roupie,
Martine Guesnu,
Mustapha Cherai,
Sylvie Gisselbrecht, and
Françoise Porteu
From the Laboratoire d'Hématopoièse, Site
Transfusionnel, the Laboratoire d'Hématologie, and the Institut
Cochin de Génétique Moléculaire (ICGM), Insitut
National de la Santé et de la Recherche Médicale (INSERM
U363), Hôpital Cochin, Université René Descartes,
Paris, France.
In several erythroleukemia cell lines, activation of
mitogen-activated protein kinases (MAPK) by phorbol esters or
megakaryocyte growth and development factor (MGDF) is required for
induction of megakaryocytic phenotype and growth arrest. To support
this model, we have examined the effect of a specific inhibitor of this
pathway (PD98059) on human CD34+ hematopoietic
progenitors isolated from cord blood (CB), induced to differentiate
along the megakaryocytic lineage in liquid cultures supplemented with
rhuMGDF. RhuMGDF induced a sustained activation of MAPK in
megakaryocytes and this activation was completely inhibited in the
presence of low concentrations of PD98059 (6 to 10 µmol/L). At this
concentration, PD98059 induced an increase in cell proliferation, resulting in accumulation of viable cells and a prolongation of the
life time of the cultures. This increase correlated with an increase in
DNA synthesis rather than with a reduction in apoptosis. This effect
was combined with developmental changes indicative of delayed
megakaryocytic differentiation: (1) PD98059-treated cells tended to
retain markers of immature progenitors as shown by the increased
proportion of both CD34+ and
CD41+CD34+ cells. (2) PD98059-treated
cultures were greatly enriched in immature blasts cells. (3) PD98059
increased megakaryocytic progenitors able to form colonies in semisolid
assays. Thus, the MAPK pathway, although not required for megakaryocyte
formation, seems to be involved in the transition from proliferation to
maturation in megakaryocytes. Inhibition of MAPK activation also led to
an increase in the number and size of erythroid colonies without
affecting granulocyte/macrophage progenitor numbers suggesting that, in addition to the megakaryocytic lineage, the MAPK pathway could play a
role in erythroid lineage differentiation.
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