Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Laboratory-Clinical Correlations: FGF-2

FGF-2 abnormalities in B cell chronic lymphocytic and chronic myeloid leukemias

Leukemia volume 15, pages 228–237 (2001)Cite this article

Abstract

An elevated level of fibroblast growth factor-2 (FGF-2) in peripheral blood is considered to play a role in regulating the growth of leukemia cells. Here, we show that the level of plasma FGF-2 is increased in 54% of B cell chronic lymphocytic leukemias (B-CLL) and in 44% of chronic myeloid leukemias (CML). Notably, white blood cells (WBCs) from B-CLL patients contain 18, 22 and 24 kDa isoforms of FGF-2 whereas WBCs from CML patients contain only the 24 kDa isoform. Furthermore, as cultured B-CLL WBCs release 18 kDa FGF-2 into the medium, they constitute a potential source of FGF-2 in the blood. In a receptor binding assay, 125I-FGF-2 binds weakly to B-CLL WBCs, whereas the ligand binds more strongly to CML WBCs. Correspondingly, FGF-2 is unable to activate mitogen-activated protein kinase kinase (MEK) and its substrate, extracellular signal-regulated kinase (ERK), in B-CLL cells, whereas phosphorylation of both these cell growth-related kinases increases following treatment of CML WBCs. We conclude that B-CLL WBCs secrete FGF-2 with no apparent autocrine actions. In contrast, WBCs in CML bind FGF-2 provided by other FGF-2-hyperproducing cells and activate the MEK/ERK kinase cascade, possibly to modulate cell growth.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Johnson DE, Williams LT . Structural and functional diversity in the FGF receptor multigene family Adv Cancer Res 1993 60: 1–41

    CAS  Google Scholar 

  2. Basilico C, Moscatelli D . The FGF family of growth factors and oncogenes Adv Cancer Res 1992 59: 115–165

    CAS  Google Scholar 

  3. Rogelj S, Weinberg RA, Fanning P, Klagsbrun M . Basic fibroblast growth factor fused to a signal peptide transforms cells Nature 1988 331: 173–175

    CAS  Google Scholar 

  4. Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J . Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers J Natl Cancer Inst 1994 86: 356–361

    CAS  Google Scholar 

  5. Duensing S, Atzpodien J . Increased intracellular and plasma levels of basic fibroblast growth factor in B-cell chronic lymphocytic leukemia Blood 1995 85: 1978–1980

    CAS  Google Scholar 

  6. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J . Spectrum of tumour angiogenesis in the bone marrow of children with acute lymphoblastic leukemia Am J Pathol 1997 150: 815–821

    CAS  Google Scholar 

  7. Hsu PI, Chow NH, Lai KH, Yang HB, Chan SH, Lin XZ, Cheng JS, Huang JS, Ger LP, Huang SM, Yen MY, Yang YF . Implications of serum basic fibroblast growth factor levels in chronic liver diseases and hepatocellular carcinoma Anticancer Res 1997 17: 2803–2810

    CAS  Google Scholar 

  8. Sasaki T, Maita E . Increased bFGF level in the serum of patients with phenytoin-induced gingival overgrowth J Clin Periodontol 1998 25: 42–47

    CAS  Google Scholar 

  9. Kadono T, Kikuchi K, Kubo M, Fujimoto M, Tamaki K . Serum concentrations of basic fibroblast growth factor in collagen diseases J Am Acad Dermatol 1996 35: 392–397

    CAS  Google Scholar 

  10. Arnaud E, Touriol C, Boutonnet C, Gensac MC, Vagner S, Prats H, Prats AC . A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor Mol Cell Biol 1999 19: 505–514

    CAS  Google Scholar 

  11. Gu XF, Bikfalvi A, Chen YZ, Caen JP, Han ZC . Constitutive and selective expression of basic fibroblast growth factor in human leukemia cell lines Eur J Haematol 1995 55: 189–194

    CAS  Google Scholar 

  12. Allouche M, Bayard F, Clamens S, Fillola G, Sie P, Amalric F . Expression of basic fibroblast growth factor (bFGF) and FGF-receptors in human leukemia cells Leukemia 1995 9: 77–86

    CAS  Google Scholar 

  13. Johnson DE, Lu J, Chen H, Werner S, Williams LT . The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain Mol Cell Biol 1991 11: 4627–4634

    CAS  Google Scholar 

  14. Avivi A, Yayon A, Givol D . A novel form of FGF receptor-3 using an alternative exon in the immunoglobulin domain III FEBS Lett 1993 330: 249–252

    CAS  Google Scholar 

  15. Feng S, Wang F, Matsubara A, Kan M, McKeehan WL . Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells Cancer Res 1997 57: 5369–5378

    CAS  Google Scholar 

  16. Drugan CS, Paterson IC, Prime SS . Fibroblast growth factor receptor expression reflects cellular differentiation in human oral squamous carcinoma cell lines Carcinogenesis 1998 19: 1153–1156

    CAS  Google Scholar 

  17. Menzel T, Rahman Z, Calleja E, White K, Wilson EL, Wieder R, Gabrilove J . Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine Blood 1996 87: 1056–1063

    CAS  Google Scholar 

  18. Prats H, Kaghad M, Prats AC, Klagsbrun M, Lelias JM, Liauzun P, Chalon P, Tauber JP, Amalric F, Smith JA, Caput D . High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG kodons Proc Natl Acad Sci USA 1989 86: 1836–1840

    CAS  Google Scholar 

  19. Bugler B, Amalric F, Prats H . Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor Mol Cell Biol 1991 11: 573–577

    CAS  Google Scholar 

  20. Bouche G, Gas N, Prats H, Baldin V, Tauber JP, Teissie J, Amalric F . Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing G0–G1 transition Proc Natl Acad Sci USA 1987 84: 6770–6774

    CAS  Google Scholar 

  21. Renko M, Quarto N, Morimoto T, Rifkin DB . Nuclear and cytoplasmic localization of different basic fibroblast growth factor species J Cell Physiol 1990 144: 108–114

    CAS  Google Scholar 

  22. Bikfalvi A, Klein S, Pintucci G, Quarto N, Mignatti P, Rifkin DB . Differential modulation of cell phenotype by different molecular weight forms of basic fibroblast growth factor: possible intracellular signaling by the high molecular weight forms J Cell Biol 1995 129: 233–243

    CAS  Google Scholar 

  23. Vagner S, Touriol C, Galy B, Audigier S, Gensac MC, Amalric F, Bayard F, Prats H, Prats AC . Translation of CUG- but not AUG-initiated forms of human fibroblast growth factor 2 is activated in transformed and stressed cells J Cell Biol 1996 135: 1391–1402

    CAS  Google Scholar 

  24. Cohen-Jonathan E, Toulas C, Monteil S, Couderc B, Maret A, Bard JJ, Prats H, Daly-Schveitzer N, Favre G . Radioresistance induced by the high molecular forms of the basic fibroblast growth factor is associated with an increased G2 delay and a hyperphosphorylation of p34CDC2 in HeLa cells Cancer Res 1997 57: 1364–1370

    CAS  Google Scholar 

  25. Couderc B, Prats H, Bayard F, Amalric F . Potential oncogenic effects of basic fibroblast growth factor requires cooperation between CUG and AUG-initiated forms Cell Regul 1991 2: 709–718

    CAS  Google Scholar 

  26. Arese M, Chen Y, Florkiewicz RZ, Gualandris A, Shen B, Rifkin DB . Nuclear activities of basic fibroblast growth factor: potentiation of low-serum growth mediated by natural or chimeric nuclear localization signals Mol Biol Cell 1999 10: 1429–1444

    CAS  Google Scholar 

  27. Brunner G, Nguyen H, Gabrilove J, Rifkin DB, Wilson EL . Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells Blood 1993 81: 631–638

    CAS  Google Scholar 

  28. Dalley A, Smith JM, Reilly JT, MacNeil S . Investigation of calmodulin and basic fibroblast growth factor (bFGF) in idiopathic myelofibrosis: evidence for a role of extracellular calmodulin in fibroblast proliferation Br J Haematol 1996 93: 856–862

    CAS  Google Scholar 

  29. Ratajczak MZ, Ratajczak J, Skorska M, Marlicz W, Calabretta B, Pletcher CH, Moore J, Gewirtz AM . Effects of basic (FGF-2) and acidic (FGF-1) fibroblast growth factor on early hematopoetic cell development Br J Haematol 1996 93: 772–782

    CAS  Google Scholar 

  30. Armstrong E, Vainikka S, Partanen J, Korhonen J, Alitalo R . Expression of fibroblast growth factor receptors in human leukemia cells Cancer Res 1992 52: 2004–2007

    CAS  Google Scholar 

  31. Katoh O, Hattori Y, Sato T, Kimura A, Kuramoto A, Sugimura T, Terada M . Expression of the heparin-binding growth factor receptor genes in human megakaryocytic leukemia cells Biochem Biophys Res Commun 1992 183: 83–92

    CAS  Google Scholar 

  32. Chandler LA, Sosnowski BA, Greenlees L, Aukerman SL, Baird A, Pierce GF . Prevalent expression of fibroblast growth factor (FGF) receptors and FGF2 in human tumour cell lines Int J Cancer 1999 81: 451–458

    CAS  Google Scholar 

  33. Bikfalvi A, Han ZC, Fuhrmann G . Interaction of fibroblast growth factor (FGF) with megakaryocytopoiesis and demonstration of FGF receptor expression in megakaryocytes and megakaryocytic-like cells Blood 1992 80: 1905–1913

    CAS  Google Scholar 

  34. Berardi AC, Wang A, Abraham J, Scadden DT . Basic fibroblast growth factor mediates its effects on committed myeloid progenitors by direct action and has no effects on hematopoietic stem cells Blood 1995 86: 2123–2129

    CAS  Google Scholar 

  35. Yamaguchi F, Saya H, Bruner JM, Morrison RS . Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas Proc Natl Acad Sci USA 1994 91: 484–488

    CAS  Google Scholar 

  36. Scotet E, Houssaint E . Exon III splicing switch of fibroblast growth factor (FGF) receptor-2 and -3 can be induced by FGF-1 or FGF-2 Oncogene 1998 17: 67–76

    CAS  Google Scholar 

  37. Liuzzo JP, Moscatelli D . Human leukemia cell lines bind basic fibroblast growth factor (FGF) on FGF receptors and heparan sulfates: downmodulation of FGF receptors by phorbol ester Blood 1996 87: 245–255

    CAS  Google Scholar 

  38. Voss J, Posern G, Hannemann JR, Wiedemann LM, Turhan AG, Poirel H, Bernard OA, Adermann K, Kardinal C, Feller SM . The leukaemic oncoprotein Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways Oncogene 2000 19: 1684–1690

    CAS  Google Scholar 

  39. Konig A, Menzel T, Lynen S, Wrazel L, Rosen A, Al-Katib A, Raveche E, Gabrilove JL . Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis Leukemia 1997 11: 258–265

    CAS  Google Scholar 

  40. Kim SC, Hahn JS, Min YH, Yoo NC, Ko YW, Lee WJ . Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1 Blood 1999 93: 3893–3899

    CAS  Google Scholar 

  41. Kang CD, Yoo SD, Hwang BW, Kim KW, Kim DW, Kim CM, Kim SH, Chung BS . The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemia K562 cells Leukemia Res 2000 24: 527–534

    CAS  Google Scholar 

Download references

Acknowledgements

We thank J Sucikova, Z Kristkova, R Slovackova and A Kozubik for their contribution to this work and E Notarianni and L Krenek for comments on manuscript. This work was supported by grant 312/97/0393 from the Grant Agency of the Czech Republic and in part by grants VS96115 and ME198 from the Ministry of Education, Youth and Sports of the Czech Republic.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Embryology, Mendel University Brno, Brno, Czech Republic

    P Krejčí, J Pacherník, A Hampl & P Dvořák

  2. Department of Internal Medicine – Hematooncology, Masaryk University Hospital, Brno, Czech Republic

    D Dvořáková, E Krahulcová & J Mayer

  3. Developmental Biology Unit, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Brno, Czech Republic

    A Hampl & P Dvořák

Authors
  1. P Krejčí
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Dvořáková
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Krahulcová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Pacherník
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Hampl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Dvořák
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krejčí, P., Dvořáková, D., Krahulcová, E. et al. FGF-2 abnormalities in B cell chronic lymphocytic and chronic myeloid leukemias. Leukemia 15, 228–237 (2001). https://doi.org/10.1038/sj.leu.2402012

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402012

Keywords

This article is cited by

Search

Advanced search

Quick links