The fibroblast growth factors in multiple myeloma (original) (raw)

Leukemia volume 20, pages 1165–1168 (2006)Cite this article

Fibroblast growth factor receptor 3 (FGFR3) is a membrane-anchored receptor tyrosine kinase that transmits intercellular signals mediated by a family of fibroblast growth factors (FGFs). In multiple myeloma (MM), 15% of patients markedly upregulate FGFR3 as a consequence of a t(4;14)(p16.3;q32) translocation.1 Ectopic expression of FGFR3 enhances MM cell proliferation and survival, demonstrating the oncogenic potential of FGFR3.2 Although a small fraction of MM cases with t(4;14)(p16.3;q32) also harbor an activating mutation in FGFR3,3 the majority upregulate wild-type FGFR3, thus depending on FGF ligand for FGFR3 activation. The human FGF family contains at least 22 members, but previous studies addressing FGF expression in MM have largely focused on FGF2. Bisping et al.4 found FGF2 to be both expressed and released by MM cells, but their results were challenged by Colla et al.,5 thus leaving the nature of the FGF ligand involved in activation of FGFR3 in MM unclear.

Among the cell lines used here, the OPM2, KMS11, KMS18, H929 and LP1 cells are known to possess t(4;14)(p16.3;q32) as well as upregulate FGFR3 (Figure 1c). We therefore asked whether FGF2 or 8 can be released by these cells lines and therefore can activate FGFR3 in an autocrine manner. We cultivated OPM2, KMS11, KMS18, H929 and LP1 cells for 72 h and purified FGF2 and 8 from the conditioned media based on their affinity for heparin (for details, see Supplementary Information). Figure 1d shows that only KMS11 and KMS18 cells release a detectable amount of FGF2 into the culture media. Although primarily nuclear, the HMW FGF2 isoforms were also released by both cell lines, similar to hairy cell leukemia.7 Although the FGF2 binding to the extracellular matrix may account for low levels of FGF2 detected in the culture media (Figure 1d), a more likely explanation is that elevated FGF2 found in the blood of MM patients originates from another cellular source than the malignant clone itself. In the media conditioned by H929 cells, the protein band of approximately 20 kDa was found (Figure 1d). This protein appears to be cross-reacting with the FGF2 antibody, as there was no FGF2 detected in the H929 cell lysates and its migration does not correspond to the known FGF2 isoforms (18, 22, 22.5 and 24 kDa bands; Figure 1b and d). No FGF8 was found in the media conditioned by any of the tested cell lines (not shown).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

References

  1. Chesi M, Nardini E, Brents LA, Schrock E, Ried T, Kuehl WM et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations in fibroblast growth factor receptor 3. Nat Genet 1997; 16: 260–264.
    Article CAS PubMed PubMed Central Google Scholar
  2. Plowright EE, Li Z, Bergsagel PL, Chesi M, Barber DL, Branch DR et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood 2000; 95: 992–998.
    CAS PubMed Google Scholar
  3. Intini D, Baldini L, Fabris S, Lombardi L, Ciceri G, Maiolo AT et al. Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14). Br J Haematol 2001; 114: 362–364.
    Article CAS PubMed Google Scholar
  4. Bisping G, Leo R, Wenning D, Dankbar B, Padro T, Kropff M et al. Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood 2003; 101: 2775–2783.
    Article CAS PubMed Google Scholar
  5. Colla S, Morandi F, Lazzaretti M, Polistena P, Svaldi M, Coser P et al. Do human myeloma cells directly produce basic FGF? Blood 2003; 102: 3071–3072.
    Article CAS PubMed Google Scholar
  6. Van den Berghe L, Laurell H, Huez I, Zanibellato C, Prats H, Bugler B . FIF (fibroblast growth factor-2 (FGF-2)-interacting-factor), a nuclear putatively antiapoptotic factor, interacts specifically with FGF-2. Mol Endocrinol 2000; 14: 1709–1724.
    Article CAS PubMed Google Scholar
  7. Gruber G, Schwarzmeier JD, Shehata M, Hilgarth M, Berger R . Basic fibroblast growth factor is expressed by CD19/CD11c-positive cells in hairy cell leukemia. Blood 1999; 94: 1077–1085.
    CAS PubMed Google Scholar
  8. Goldfarb M . Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Rev 2005; 16: 215–220.
    Article CAS PubMed PubMed Central Google Scholar

Download references

Acknowledgements

This work was supported by Multiple Myeloma Foundation and Yang Sheng Tang USA Company.

Author information

Authors and Affiliations

  1. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    P Krejci, P B Mekikian & W R Wilcox
  2. Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA, USA
    W R Wilcox

Authors

  1. P Krejci
    You can also search for this author inPubMed Google Scholar
  2. P B Mekikian
    You can also search for this author inPubMed Google Scholar
  3. W R Wilcox
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toP Krejci.

Additional information

Supplementary information

Rights and permissions

About this article

Cite this article

Krejci, P., Mekikian, P. & Wilcox, W. The fibroblast growth factors in multiple myeloma.Leukemia 20, 1165–1168 (2006). https://doi.org/10.1038/sj.leu.2404202

Download citation

This article is cited by