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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3274-3282
HEMATOPOIESIS
Role of p21Cip1/Waf1 in cell-cycle
exit of endomitotic megakaryocytes
Véronique Baccini,
Lydia Roy,
Natacha Vitrat,
Hédia Chagraoui,
Siham Sabri,
Jean-Pierre Le Couedic,
Najet Debili,
Françoise Wendling, and
William Vainchenker
From INSERM U 362, Institut Gustave Roussy, Villejuif,
France.
The cyclin-dependent kinase inhibitor p21Waf-1/Cip-1 is
expressed at high level during megakaryocyte differentiation, but its
precise function remains unknown. In this study, it is
confirmed that p21 was expressed at a high level in hypoploid
(2N and 4N) and polyploid (at least 8N) human megakaryocytes
derived from CD34+ cells. A high expression of
p27Kip1, p16, cyclin E, and cyclin D3 was also found in
both populations associated with a hypophosphorylated form of
retinoblastoma protein, suggesting that the majority of
hypoploid and polyploid megakaryocytes are
G1-arrested cells. As human megakaryocytes grown in vitro present a defect in their polyploidization, the study switched to
the murine model. The modal ploidy of megakaryocytes derived from
lineage-negative cells was 32N, and an elevated expression of p21
was found in high-ploidy megakaryocytes. In addition, p21 and p27 were
coexpressed in the majority of mature polyploid megakaryocytes. The
p21 was detected by immunofluorescence in megakaryocytes
derived from p53 / mice, demonstrating a p53-independent
regulation during megakaryocyte differentiation. Megakaryocytopoiesis
of p21/ mice was subsequently studied. No marked
abnormality in the ploidy of primary or cultured megakaryocytes was
detected. Overexpression of p21 in p21/ or normal
murine megakaryocytes and in human megakaryocytes showed in all these
cases a marked inhibition in megakaryocyte polyploidization. In
conclusion, while a reciprocal relation is observed between p21 levels
in megakaryocytes and the cycling state of the cells, p21 is not
essential for the determination of the ploidy profile in normal
megakaryocytes in vivo. However, high levels of its expression in
cultured megakaryocytes arrest the endomitotic cell cycle.
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