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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3011-3016
HEMATOPOIESIS
Shwachman-Diamond syndrome marrow cells show abnormally increased
apoptosis mediated through the Fas pathway
Yigal Dror and
Melvin H. Freedman
From the Department of Pediatrics, Division of
Hematology and Oncology, Research Institute, The Hospital for Sick
Children, University of Toronto, Ontario, Canada.
Shwachman-Diamond syndrome (SDS) is an inherited bone marrow
disorder with varying cytopenias and a strong predilection to myelodysplastic syndrome (MDS) and acute myeloid leukemia. Previously, it was found that the percentage of CD34+ cells in bone
marrow and the in vitro colony formation from CD34+ cells
of patients with SDS were markedly reduced. For these reasons, and
because apoptosis is central in the pathogenesis of bone marrow dysfunction in MDS, this study was initiated to delineate the role of
apoptosis in the pathogenesis of the marrow failure. Eleven children
with SDS were studied. Compared to normal controls, patients' marrow
mononuclear cells plated in clonogenic cultures showed a significantly
higher tendency to undergo apoptosis. The defect in SDS was found in
patients with and without MDS. Patients showed a more prominent
decrease in colony formation and increased apoptosis after
preincubation with activating anti-Fas antibody. Fas expression on
marrow cells from patients was significantly higher than from normal
controls. The difference between patients and controls for Fas
expression was also significant for the following cell fraction
subpopulations: CD34 /CD38,
CD34/CD38+, and CD34+. In
conclusion, SDS hematopoietic progenitors are intrinsically flawed and
have faulty proliferative properties and increased apoptosis. Bone
marrow failure in SDS appears mediated by increased apoptosis as the
central pathogenetic mechanism. This increased propensity for apoptosis
is linked to increased expression of the Fas antigen and to
hyperactivation of the Fas signaling pathway.
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