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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1633-1641
Existence of a differentiation blockage at the stage of a
megakaryocyte precursor in the thrombocytopenia and absent radii (TAR)
syndrome
Rémi Letestu,
Natacha Vitrat,
Aline Massé,
Jean-Pierre Le Couedic,
Vladimir Lazar,
Philippe Rameau,
Françoise Wendling,
Jacqueline Vuillier,
Patrick Boutard,
Emmanuel Plouvier,
Mireille Plasse,
Rémi Favier,
William Vainchenker, and
Najet Debili
From INSERM U 362, Laboratoire associé no. 5 du comité
de Paris de la Ligue Nationale, Institut Gustave Roussy, Villejuif,
France; Plateau technique, Institut Gustave Roussy, Villejuif, France;
Service d'hématologie, CHU Jean Minjoz, Besançon, France;
Service d'hématologie, CHU Côte de Nacre, Caen, France;
Unité d'hématologie infantile, CHU St Jacques,
Besançon, France; Service de pédiatrie, centre hospitalier
d'Albertville, Albertville, France; and Service d'hématologie
biologique, Hôpital Armand Trousseau, Paris, France.
The thrombocytopenia and absent radii (TAR) syndrome is a rare
disease associating bilateral radial agenesis and congenital thrombocytopenia. Here, we investigated in vitro megakaryocyte (MK)
differentiation and expression of c-mpl in 6 patients. Using blood or
marrow CD34+ cells, the colony-forming unit (CFU)-MK
number was markedly reduced. CD34+ cells were also
cultured in liquid medium in the presence of a combination of 3 cytokines (stem cell factor, interleukin-3, and interleukin-6) or
megakaryocyte growth and development factor (PEG-rHuMGDF) with or
without SCF. In the presence of PEG-rHuMGDF, the majority of mature
megakaryocytes (CD41 high, CD42 high) underwent apoptosis. This
phenomenon was also observed in cultures stimulated by three cytokines.
However, this last combination of cytokines allowed a more complete
terminal MK differentiation. Surprisingly, a homogeneous population of
CD34-CD41+CD42- cells accumulated
during the cultures. This population was unable to differentiate along
the myeloid pathways. This result suggests that a fraction of MK cells
is unable to differentiate in the TAR syndrome. We subsequently
investigated whether this could be related to an abnormality in c-mpl.
No mutation or rearrangement in the c-mpl gene was found by
Southern blots or by sequencing of the c-mpl coding region and its
promoter in any of the patients. Using Western blot analysis, a
decreased level of Mpl was found in patient platelets. A decreased
level of c-mpl messenger RNA in TAR platelets was also detected with a
lower c-mpl-P to c-mpl-K ratio in comparison to adult platelets.
Altogether, these results demonstrate that the thrombocytopenia of the
TAR syndrome is associated with a dysmegakaryocytopoiesis characterized
by cells blocked at an early stage of differentiation.
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