Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3048-3054
Shwachman-Diamond Syndrome: An Inherited Preleukemic Bone Marrow
Failure Disorder With Aberrant Hematopoietic Progenitors and Faulty
Marrow Microenvironment
Yigal Dror and
Melvin H. Freedman
From the Division of Hematology and Oncology and the Research
Institute, The Hospital for Sick Children, and the University of
Toronto, Toronto, Ontario, Canada.
Shwachman-Diamond syndrome (SD), an inherited disorder with varying
cytopenias and a marked tendency for malignant myeloid transformation,
is an important model for understanding genetic determinants in
hematopoiesis. To define the basis for the faulty hematopoietic
function, 13 patients with SD (2 of whom had myelodysplasia with a
clonal cytogenetic abnormality) and 11 healthy marrow donors were
studied. Patients with SD had significantly lower numbers of
CD34+ cells on bone marrow aspirates. SD
CD34+ cells plated directly in standard clonogenic assays
showed markedly impaired colony production potential, underscoring an
intrinsically aberrant progenitor population. To assess marrow stromal
function, long-term marrow stromal cell cultures (LTCs) were
established. Normal marrow CD34+ cells were plated over
either SD stroma (N/SD) or normal stroma (N/N); SD CD34+
cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of
granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD
nonadherent cells were also lower. SD/N showed improved production of
nonadherent cells and CFU-GM colonies compared with SD/SD, but much
less than N/N. Stem-cell and stromal properties from the 2 patients
with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia. We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability
to support and maintain hematopoiesis. This dual defect exists in SD
with and without myelodysplasia.
