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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1077-1085
Basic Fibroblast Growth Factor Is Expressed by CD19/CD11c-Positive
Cells in Hairy Cell Leukemia
Gerhard Gruber,
Josef D. Schwarzmeier,
Medhat Shehata,
Martin Hilgarth, and
Rudolf Berger
From the Ludwig Boltzmann Institute for Cytokine Research and the
Department of Internal Medicine I, Division of Hematology, University
of Vienna Medical School, Vienna, Austria.
Several features are characteristic for hairy cell leukemia (HCL).
Among those are pancytopenia, bone marrow fibrosis, and the appearance
of a defined tumor cell phenotype in peripheral blood (PB), bone marrow
(BM), and spleen. Hairy cells (HC) coexpress antigens specific for B
lymphocytes and monocytes/macrophages and thus the malignant cell does
not seem to be restricted to a defined lineage. When serum or bone
marrow aspirate was screened by enzyme-linked immunosorbent assay
(ELISA) for basic fibroblast growth factor (bFGF), specimen derived
from HCL (serum: mean value, 29 pg/mL; BM aspirate: mean value, 641 pg/mL) contained significantly higher levels than those from healthy
subjects. To study whether peripheral blood mononuclear cells (PBMC)
derived from patients suffering from HCL and healthy donors (HD) were
capable of producing bFGF, culture supernatant (conditioned medium,
[CM]) was tested for the presence of this cytokine. While bFGF was
not detectable in cell cultures from HD, HCL-derived CM contained
relatively high levels of bFGF. CM was successfully used for
stimulation of mesenchymal cell proliferation, which could be inhibited
by a neutralizing anti-bFGF antibody. Cellular activation by pokeweed mitogen (PWM) or the combination of
12-o-tetradecanoyl-phorbol-13-acetate (TPA) plus calcium ionophore
(Ca-Ip) led to an enhanced mRNA expression. Results of Western blot
experiments showed that HC synthesize at least three isoforms
(approximately 18, 23, and 25 kD), but only the 23-kD isoform is
exported. To assess the nature of the producer cell, double
immunofluorescence analysis using a bFGF-specific and an anti-CD11c
monoclonal antibody (MoAb) was undertaken. The majority of cells
scoring positive for CD11c were also reactive with the anti-bFGF MoAb.
Furthermore, enrichment of CD19/CD11c-positive cells correlated with
enhanced bFGF levels, thereby supporting the argument for HC being the
producer cells of bFGF. A biological function of bFGF in HCL might be
mediation of chemoresistance, as 2-chlorodeoxyadenosine
(2-CdA)-induced inhibition of cell proliferation can be reversed by
bFGF. Endogenous bFGF production by HC is not affected by this purine
analogue and 2-CdA-induced apoptosis is diminished in bFGF-producing
HC as compared with normal PBMC. Therefore, bFGF expression by HC might
be important for resistance to chemotherapy and survival of the
malignant cells.
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