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 Article
  • Published:

Molecular Targets for Therapy

Correlation of neuropilin-1 overexpression to survival in acute myeloid leukemia

Abstract

Neuropilin-1 (NRP-1), a vascular endothelial growth factors and semaphorin receptor functioning as mediator of angiogenesis and neuronal guidance, is expressed by various solid tumors. The importance of NRP-1 in hematological malignancies such as acute myeloid leukemia (AML) remains to be elucidated. Therefore, we determined NRP-1 expression by immunohistochemical analysis of bone marrow biopsies of patients with newly diagnosed, untreated AML. The expression of NRP-1 was significantly increased in AML patients (n=76; median 12.9 arbitrary units (a.u.)) as compared with controls (n=38; median 2.75 a.u.). Survival was significantly poorer in patients with high (>median) versus low (median) NRP-1 expression levels with 5-year overall survival rates of 16.9 versus 49.6% (P=0.050). In conclusion, our data provide evidence of increased NRP-1 expression in AML with significant correlation to survival. Thus, NRP-1 might constitute a promising target for antileukemic and antiangiogenic treatment strategies in AML.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Padro T, Ruiz S, Bieker R, Bürger H, Steins M, Kienast J et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 2000; 95: 2637–2644.

    CAS  Google Scholar 

  2. Padro T, Bieker R, Ruiz S, Steins M, Bürger H, Büchner T et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 2002; 16: 1302–1310.

    Article  CAS  Google Scholar 

  3. Bieker R, Padro T, Kramer J, Steins M, Kessler T, Retzlaff S et al. Overexpression of basic fibroblast growth factor and autocrine stimulation in acute myeloid leukemia. Cancer Res 2003; 63: 7241–7246.

    CAS  PubMed  Google Scholar 

  4. Hussong JW, Rodgers GM, Shami PJ . Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000; 95: 309–313.

    CAS  Google Scholar 

  5. Loges S, Heil G, Bruweleit M, Schoder V, Butzal M, Fischer U et al. Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival. J Clin Oncol 2005; 23: 1109–1117.

    Article  CAS  Google Scholar 

  6. Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M . Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res 2006; 312: 584–593.

    Article  CAS  Google Scholar 

  7. Tordjman R, Ortega N, Coulombel L, Plouet J, Romeo PH, Lemarchandel V . Neuropilin-1 is expressed on bone marrow stromal cells: a novel interaction with hematopoietic cells ? Blood 1999; 94: 2301–2309.

    CAS  PubMed  Google Scholar 

  8. Belaid Z, Hubint F, Humblet C, Boniver J, Nusgens B, Defresne MP . Differential expression of vascular endothelial factor and its receptors in hematopoietic and fatty bone marrow: evidence that neuropilin-1 is produced by fat cells. Haematologica 2005; 90: 400–401.

    CAS  PubMed  Google Scholar 

  9. Yamada Y, Oike Y, Ogawa H, Ito Y, Fujisawa H, Suda T et al. Neuropilin-1 on hematopoietic cells as a source of vascular development. Blood 2003; 101: 1801–1809.

    Article  CAS  Google Scholar 

  10. Fons P, Herault JP, Delesque N, Tuyaret J, Bono F, Herbert JM . VEGF-R2 and neuropilin-1 are involved in VEGF-A induced differentiation of human bone marrow progenitor cells. J Cell Physiol 2004; 200: 351–359.

    Article  CAS  Google Scholar 

  11. Schuch G, Machluf M, Bartsch G, Nomi M, Richard H, Atala A et al. In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood 2002; 100: 4622–4628.

    Article  CAS  Google Scholar 

  12. Buchner T, Hiddemann W, Wormann B, Loffler H, Gassmann W, Haferlach T et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 1999; 93: 4116–4124.

    CAS  PubMed  Google Scholar 

  13. Harper SJ, Xing CY, Whittle C, Parry R, Gillatt D, Peat D et al. Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo. Clin Science 2001; 101: 439–446.

    Article  CAS  Google Scholar 

  14. Moehler TM, Ho AD, Goldschmidt H, Barlogie B . Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol 2003; 45: 227–244.

    Article  CAS  Google Scholar 

  15. Aref S, El Sherbina M, Goda T, Fouda M, Al Askalany H, Abdalla D . Soluble VEGF/sFLt1 ratio is an independent predictor of AML patient out come. Hematology 2005; 10: 131–134.

    Article  CAS  Google Scholar 

  16. Aguayo A, Estey EH, Kantarjian HM, Manshouri T, Gidel C, Keating M et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukaemia. Blood 1999; 94: 3717–3721.

    CAS  Google Scholar 

  17. Aguayo A, Kantarjian HM, Estey EH, Giles FJ, Verstovsek S, Manshouri T et al. Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer 2002; 95: 1923–1930.

    Article  Google Scholar 

  18. Kamiya T, Kawakami T, Abe Y, Nishi M, Onoda N, Miyazaki N et al. The preserved expression of neuropilin 1 contributes to a better prognosis in colon cancer. Oncol Rep 2006; 15: 369–373.

    CAS  PubMed  Google Scholar 

  19. Osada H, Tokunaga T, Nishi M, Hatanaka H, Abe Y, Tsugu A et al. Overexpression of the neuropilin 1 gene correlated with poor prognosis in human glioma. Anticancer Res 2004; 24: 547–552.

    CAS  PubMed  Google Scholar 

  20. Kawakami T, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Abe Y et al. Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer 2002; 95: 2196–2201.

    Article  CAS  Google Scholar 

  21. Soker S, Miao HQ, Nomi M, Takashima S, Klagsbrun M . VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem 2002; 85: 357–368.

    Article  CAS  Google Scholar 

  22. Miao HQ, Lee P, Lin H, Soker S, Klagsbrun M . Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J 2000; 14: 2532–2539.

    Article  CAS  Google Scholar 

  23. Dias S, Hattori K, Heissig B, Zhu Z, Wu Y, Witte L et al. Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci USA 2001; 98: 10857–10862.

    Article  CAS  Google Scholar 

  24. Bachelder RE, Crago A, Chung J, Wendt MA, Shaw LM, Robinson G et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res 2001; 61: 5736–5740.

    CAS  PubMed  Google Scholar 

  25. Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastastic tumor phenotype. J Clin Invest 2004; 114: 1260–1271.

    Article  CAS  Google Scholar 

  26. Wang Z, Li Y, Wu X, Cheng S, Yang L, Wu Y . KDR and Sema3 genes expression in bone marrow stromal cells and hematopoietic cells from leukaemia patients and normal individuals. Hematology 2005; 10: 307–312.

    Article  CAS  Google Scholar 

  27. Bennet JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Granlnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group. Ann Intern Med 1985; 103: 620–626.

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to Mrs Margret Lindermann, Department of Medicine/Hematology and Oncology for her excellent technical support, to Dr Joachim Gerss, Coordinating Centre for Clinical Trials for his statistical advice and to Dr Horst Buerger, Gerhard-Domagk Institute of Pathology, University of Muenster, Germany. This work was supported by grants from the ‘Deutsche Forschungsgemeinschaft’ (Me 950/3-2) and the program ‘Innovative Medizinische Forschung’ (KR 110303) of the Medical Faculty at the University of Muenster, Germany.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R M Mesters.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kreuter, M., Woelke, K., Bieker, R. et al. Correlation of neuropilin-1 overexpression to survival in acute myeloid leukemia. Leukemia 20, 1950–1954 (2006). https://doi.org/10.1038/sj.leu.2404384

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404384

Keywords

This article is cited by

Search

Quick links