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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-12-3737.
Submitted December 9, 2002
Accepted April 1, 2003
The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukaemia (HCL)
Khalil A Aziz, Kathleen J Till*, Haijuan Chen, Joseph R Slupsky, Fiona Campbell, John C Cawley, and Mirko Zuzel
Haematology, University of Liverpool, Liverpool, United Kingdom
Pathology, University of Liverpool, Liverpool, United Kingdom
* Corresponding author; email: k.j.till{at}liv.ac.uk.
Bone marrow (BM) fibrosis is a central diagnostic and pathogenetic feature of hairy-cell leukaemia (HCL). It is known that fibronectin (FN) produced and assembled by the malignant hairy cells (HCs) themselves is a major component of this fibrosis. It is also known that FN production is greatly enhanced by adhesion of HCs to hyaluronan (HA) via CD44. The aim of the present study was to establish the roles of fibrogenic autocrine cytokines (FGF-2 and TGF ) and of different isoforms of CD44 in this FN production. We show that HC adhesion to HA stimulates FGF-2, but not TGF, production and that HCs possess FGF-2 receptor. In a range of experiments, FN production was greatly reduced by blocking FGF-2, but not TGF. Moreover FN, but not FGF-2, secretion was blocked by down regulation of the v3 isoform of CD44 and by addition of heparitinase. These results show that autocrine FGF-2 secreted by HCs is the principal cytokine responsible for FN production by these cells when cultured on HA. The central role of FGF-2 in the pathogenesis of the BM fibrosis of HCL was supported by our immunohistochemical demonstration of large amounts of this cytokine in fibrotic BM, but not in HCL spleen where there is no fibrosis. As regards CD44 isoforms, the present work demonstrates that CD44v3 is essential for providing the heparan sulphate necessary for HC stimulation by FGF-2, whereas the signal for production of the cytokine was provided by HA binding to CD44H, the standard haematopoietic form of the molecule.
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