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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1594-1601
HEMATOPOIESIS
In vitro proliferation and differentiation of erythroid
progenitors from patients with myelodysplastic syndromes: evidence for
Fas-dependent apoptosis
Yann-Erick Claessens,
Didier Bouscary,
Jean-Michel Dupont,
Françoise Picard,
Josiane Melle,
Sylvie Gisselbrecht,
Catherine Lacombe,
François Dreyfus,
Patrick Mayeux, and
Michaëla Fontenay-Roupie
From the Department of Hematology, AP-HP, Hôpital
Cochin; INSERM U363, Institut Cochin de Génétique
Moléculaire, Université René-Descartes, Paris V; and
the Laboratory of Histology Embryology and Cytogenetics, AP-HP,
Hôpital Cochin, Paris, France.
Erythropoiesis results from the proliferation and differentiation
of pluripotent stem cells into immature erythroid progenitors (ie,
erythroid burst-forming units (BFU-Es), whose growth, survival, and
terminal differentiation depends on erythropoietin (Epo). Ineffective
erythropoiesis is a common feature of myelodysplastic syndromes (MDS).
We used a 2-step liquid-culture procedure to study erythropoiesis in
MDS. CD34+ cells from the marrow of patients with MDS were
cultured for 10 days in serum-containing medium with Epo, stem cell
factor, insulinlike growth factor 1, and steroid hormones until they
reached the proerythroblast stage. The cells were then placed in medium containing Epo and insulin for terminal erythroid differentiation. Numbers of both MDS and normal control cells increased 103
fold by day 15. However, in semisolid culture, cells from patients with
refractory anemia (RA) with ringed sideroblasts and RA or RA with
excess of blasts produced significantly fewer BFU-Es than cells from
controls. Fluorescence in situ hybridization analysis of interphase
nuclei from patients with chromosomal defects indicated that abnormal
clones were expanded in vitro. Epo-signaling pathways (STAT5, Akt, and
ERK 1/2) were normally activated in MDS erythroid progenitors. In
contrast, apoptosis was significantly increased in MDS cells once they
differentiated, whereas it remained low in normal cells. Fas was
overexpressed on freshly isolated MDS CD34+ cells and on
MDS erythroid cells throughout the culture. Apoptosis coincided with
overproduction of Fas ligand during the differentiation stage and was
inhibited by Fas-Fc chimeric protein. Thus, MDS CD34+-derived erythroid progenitors proliferated normally
in our 2-step liquid culture with Epo but underwent abnormal
Fas-dependent apoptosis during differentiation that could be
responsible for the impaired erythropoiesis.
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