The role of autocrine FGF-2 in the distinctive bone marrow fibrosis of hairy-cell leukemia (HCL)

Abstract

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 ␤ [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 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.

Comprehensive genetic and functional characterization of IPH‐926: a novel CDH1‐null tumour cell line from human lobular breast cancer

“…However, in comparison to other established breast cancer cell lines, IPH-926 cells did not display significant overexpression of FGFR1 mRNA ( Figure 7D). In fact, FGFR1 protein expression was barely detectable in IPH-926 cells by western blotting of 30 µg of total cellular proteins separated by SDS-PAGE using the well-established monoclonal anti-FGFR1 antibody M19B2 ( Figure 7E) [44]. This was additionally confirmed with another anti-FGFR1 antibody, 10646, whose specificity has also previously been demonstrated ( Figure 7F) [10].…”

Activation of FGFR1β signaling pathway promotes survival, migration and resistance to chemotherapy in acute myeloid leukemia cells

“…[6][7][8] Although the results were somewhat conflicting in regard to FGFR expression patterns for each cell line, the data suggest that most AML cell lines express at least one of the four FGFRs. Because of the typically low receptor density of tyrosine kinase receptors, detection on a protein level by standard methods such as flow cytometry 20 or Western blot without immunoprecipitation has been a daunting task. In addition, FGFRs may be cleaved 21 and/or internalized 22 as part of the signaling mechanism, further complicating receptor detection.…”

TGF-β1 induces bone marrow reticulin fibrosis in hairy cell leukemia

“…In addition to reticulin fibrosis, it has been recently demonstrated that the glycoprotein fibronectin, which is produced and assembled by HCs, contributes to the fibrotic process in BM of HCL patients (19). This process was also found to be particularly enhanced by bFGF, which is endogenously produced by the HCs (20). Since reticulin and fibronectin fibers were found to represent different structures in myelofibrotic BM (21), it appears that BM fibrosis in HCL is a complex process that involves accumulation and assembly of collagenous ECM components (reticulin) (22) and noncollagenous ECM components (fibronectin).…”