The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukemia (HCL).
Bone marrow (BM) fibrosis is a central diagnostic and pathogenetic feature of hairy-cell leukemia (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 (fibroblast growth factor-2 [FGF-2] and transforming growth factor beta [TGFbeta]) and of different isoforms of CD44 in this FN production. We show that HC adhesion to HA stimulates FGF-2, but not TGFbeta, production and that HCs possess FGF-2 receptor. In a range of experiments, FN production was greatly reduced by blocking FGF-2 but not TGFbeta. 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 sulfate necessary for HC stimulation by FGF-2, whereas the signal for production of the cytokine was provided by HA binding to CD44H, the standard hematopoietic form of the molecule.
Aziz
Khalil A
KA
Department of Haematology, University of Liverpool, Liverpool, United Kingdom.
Till
Kathleen J
KJ
Chen
Haijuan
H
Slupsky
Joseph R
JR
Campbell
Fiona
F
Cawley
John C
JC
Zuzel
Mirko
M
D019898:Autocrine Communication; D002448:Cell Adhesion; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D005353:Fibronectins / Q000096:biosynthesis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000502:physiology; D006820:Hyaluronic Acid / Q000378:metabolism; D007943:Leukemia, Hairy Cell / Q000378:metabolism / Q000473:pathology*; D055728:Primary Myelofibrosis / Q000209:etiology* / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
C121450:CD44V3,8-10; D005353:Fibronectins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D006820:Hyaluronic Acid; C496353:FGFR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2