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Excessive production of transforming growth factor-beta by bone marrow
stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of
hematopoietic precursors and interleukin-6 production
L Lagneaux, A Delforge, C Dorval, D Bron and P Stryckmans
Service de Medecine Interne, Institut J. Bordet, Brussels, Belgium.
To explore the pathogenesis of marrow failure in B-cell type chronic
lymphocytic leukemia (B-CLL), we have examined the production of
interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and
granulocyte-macrophage CSF (GM-CSF) by the adherent cell population of bone
marrow (BM) derived from B-CLL patients and their capacity to support
hematopoietic cell proliferation. Lipopolysaccharide-stimulated B-CLL
stromal cells produced G-CSF and GM-CSF in amounts similar to normal
stromal layers, whereas IL-6 production was significantly decreased. Using
the blast-colony forming cell assay (BI-CFC) and the classical
colony-forming unit granulocyte macrophage (CFU-GM) assay, we found that:
(1) marrow stromal cells of B-CLL were able to support only 25% of the
BI-CFC growth supported by normal marrow stromal cells; (2) this anomaly
was partially corrected by the addition of exogenous IL-6; (3) the
colony-stimulating activity (CSA) of the conditioned medium (CM) of B-CLL
stromal cells was lower than that of normal CM; (4) that this was the
result of the presence of an inhibitor rather that of a growth factor
defect; (5) this inhibition could be abrogated by addition of
anti-transforming growth factor-beta (TGF-beta) neutralizing antibody; (6)
this antibody corrected the deficient colony supportive activity of the
B-CLL stromal cells; (7) TGF-beta production by marrow stromal cells was
significantly increased in CLL compared with normal; and (8) that this was
not caused by the effect of the B- CLL lymphocytes on the stromal cells. It
is concluded that this increased TGF-beta production in B-CLL is probably
responsible for the decreased IL-6 production by stromal cells and for the
inhibiting activity on hematopoietic precursors as well. We hypothesize
that TGF- beta generated at a high level by B-CLL marrow stromal cells
could play a major role in the pathophysiology of the BM failure seen in
advanced stages of B-CLL.
Volume 82,
Issue 8,
pp. 2379-2385,
10/15/1993
Copyright © 1993 by The American Society of Hematology
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