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Severe congenital neutropenia: abnormal growth and differentiation of
myeloid progenitors to granulocyte colony-stimulating factor (G-CSF) but
normal response to G-CSF plus stem cell factor
K Hestdal, K Welte, SO Lie, JR Keller, FW Ruscetti and TG Abrahamsen
Department of Pediatric Research, Rikshospitalet, National Hospital, Oslo,
Norway.
Several mechanisms have been proposed to explain the pathogenesis of severe
congenital neutropenia (SCN); however, the mechanism(s) still remains
unknown. In particular, clinical observations suggest that abnormal
responsiveness of myeloid progenitors to hematopoietic growth factors
(HGFs) is a possible mechanism. Therefore, to better define the status of
hematopoietic progenitors in the bone marrow (BM) of patients with SCN, the
responsiveness of myeloid progenitors to HGFs from two SCN patients was
compared with the responsiveness of progenitors from healthy individuals.
BM cells (BMCs) from the first SCN patient required higher (10- to
100-fold) concentrations of granulocyte colony- stimulating factor (G-CSF)
to achieve maximal and half-maximal colony growth in vitro compared with
BMCs from controls. In contrast, the dose- response of interleukin-3 (IL-3)
and granulocyte-macrophage-CSF (GM- CSF) in colony formation was normal.
Interestingly, IL-3, GM-CSF, and G- CSF at optimal doses showed reduced
ability to induce neutrophil differentiation of BMCs from a SCN patient
compared with BMCs from controls. Despite an abnormal responsiveness of
mature myeloid progenitors to G-CSF in this SCN patient, myeloid
progenitors responsive to the combination of stem cell factor (SCF) and
G-CSF showed normal dose-response. In contrast to G-CSF alone, the
combination of G-CSF and SCF induced the formation of neutrophils almost to
the same extent compared with cultures of normal BMCs. Furthermore, also on
BM progenitor cells obtained from the second patient with SCN, SCF highly
synergized with G-CSF to promote neutrophil progenitor cell growth and
differentiation in vitro. Thus, these results indicate that one mechanism
of the pathogenesis in SCN patients is reduced responsiveness of neutrophil
progenitor cells to G- CSF and that SCF can enhance the responsiveness of
these cells to G-CSF.
Volume 82,
Issue 10,
pp. 2991-2997,
11/15/1993
Copyright © 1993 by The American Society of Hematology
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