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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4077-4083
Defective Proliferation of Primitive Myeloid Progenitor Cells in
Patients With Severe Congenital Neutropenia
Nakao Konishi,
Masao Kobayashi,
Shin-ichiro Miyagawa,
Takashi Sato,
Osamu Katoh, and
Kazuhiro Ueda
From The Department of Pediatrics, Hiroshima University School of
Medicine, Hiroshima; The Department of Child Health, Faculty of
Education, and Department of Environment and Mutation, Research
Institute for Radiation Biology and Medicine, Hiroshima University,
Hiroshima, Japan.
Although several mechanisms have been proposed to explain the
pathophysiology of severe congenital neutropenia (SCN), the precise
defect responsible for SCN remains unknown. We studied the
responsiveness of primitive myeloid progenitor cells to hematopoietic factors in 4 patients with SCN. The number of granulocyte-macrophage (GM) colonies formed in patients was decreased in response to granulocyte colony-stimulating factor (G-CSF) in both
serum-supplemented and serum-deprived culture. The polymerase chain
reaction-single-strand conformational polymorphism analysis of the
G-CSF receptor gene showed no variance in structure conformation
between the 4 patients and the normal subjects. In patients with SCN,
the nonadherent light density bone marrow cells and cells that were
purified on the basis of the expression of CD34 and Kit receptor
(CD34+/Kit+ cells) showed the reduced
response to the combination of steel factor (SF), the ligand for
flk2/flt3 (FL), and interleukin-3 (IL-3) with or without G-CSF in
serum-deprived culture. Furthermore, when individual
CD34+/Kit+ cells from patients were
cultured in the presence of SF, FL, and IL-3, with or without G-CSF for
10 days, the number of clones proliferated and the number of cells per
each proliferating clone was significantly less than those in normal
subjects. These results suggest that primitive myeloid progenitor cells
of patients with SCN have defective responsiveness to not only G-CSF,
but also the early- or intermediate-acting hematopoietic factors, SF,
FL, and IL-3.
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