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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2595-2604
Mechanism of flt3 Ligand Expression in Bone Marrow Failure:
Translocation From Intracellular Stores to the Surface of T
Lymphocytes After Chemotherapy-Induced Suppression of Hematopoiesis
Elena Chklovskaia,
Wendy Jansen,
Catherine Nissen,
Stewart D. Lyman,
Christoph Rahner,
Lukas Landmann, and
Aleksandra Wodnar-Filipowicz
From the Department of Research, University Hospital Basel,
Switzerland; IMMUNEX Corp, Seattle, WA; and the Institute of Anatomy,
University of Basel, Basel, Switzerland.
The flt3 ligand (FL) is a growth factor for primitive hematopoietic
cells. Serum levels of FL are inversely related to the number and
proliferative capacity of early hematopoietic progenitors. We sought to
elucidate the molecular mechanism underlying this regulation.
Expression of FL was examined in peripheral blood (PB) and bone marrow
(BM) cells under normal steady-state hematopoiesis and during transient
BM failure induced by chemoradiotherapy in 16 patients with
hematological malignancies. Using anti-FL antibodies in Western
analysis, flow cytometry, and confocal microscopy, we detected high
levels of preformed FL inside but not on the surface of T lymphocytes
in steady-state hematopoiesis. Intracellular FL colocalized with
giantin and ERGIC-53, indicating that it is stored within and close to
the Golgi apparatus. After chemotherapy-induced hematopoietic failure,
FL rapidly translocated to the surface of T lymphocytes and the levels
of FL released to serum increased approximately 100-fold. Expression of
FL mRNA was enhanced only about sevenfold; a similar, twofold to
sixfold increase in mRNA was observed in the thymus and BM of mice with
irradiation-induced aplasia. Upregulation of FL mRNA was delayed when
compared with the appearance of cell surface-associated and soluble
protein isoforms. The described changes in FL expression in response to chemotherapy-induced aplasia were observed in all patients,
irrespective of the diagnosis and treatment regimen. Our data
demonstrate that mobilization of preformed FL from intracellular stores
rather than de novo synthesis is responsible for increased FL levels in
BM failure.
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