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.

  • Spotlight
  • Published:

VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance

Leukemia volume 19, pages 513–523 (2005)Cite this article

A Corrigendum to this article was published on 14 April 2010

Abstract

We have previously shown that chronic lymphocytic leukemia (CLL) B cells secrete vascular endothelial growth factor (VEGF) in vitro, have constitutively active VEGF receptors R1 and R2, and respond to exogenous VEGF by specifically upregulating Mcl-1 and XIAP in association with decreased cell death. We found that epigallocatechin (EGCG) decreases VEGF receptor phosphorylation and induces apoptosis in CLL B cells. The mechanism(s) by which VEGF receptor activation increases Mcl-1 and XIAP and promotes survival remains unknown. To further define the signaling pathway mediating VEGF induction of antiapoptotic proteins in CLL B-cells, we investigated downstream effects of VEGF–VEGF receptor binding on the STAT signaling pathway. We find that CLL B cells abundantly express cytoplasmic serine phosphorylated (p)-STAT-1 and p-STAT-3, VEGF-R1/2 are physically associated with p-STAT-1 and p-STAT-3, and p-STAT-3 (but not p-STAT-1) is found in the CLL nucleus. VEGF receptor ligation selectively induces activation and perinuclear translocation of STAT 3 through receptor-mediated endocytosis. The inhibition of VEGF receptor activation with either tyrosine kinase inhibitors or VEGF neutralizing antibodies inhibit VEGF receptor phosphorylation, decrease p-STAT-3 (serine 727), Mcl-1, and induces cell death in CLL B cells. Thus, a VEGF–VEGF receptor pathway in CLL B cells can be linked to activation of STAT proteins that are able to enhance their apoptotic resistance.

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

Relevant articles

Open Access articles citing this article.

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
Figure 7
Figure 8

References

  1. Kipps TJ . Chronic lymphocytic leukemia [Review] [124 refs]. Curr Opin Hematol 1998; 5: 244–253.

    Article  CAS  PubMed  Google Scholar 

  2. Keating MJ . Chronic lymphocytic leukemia [Review] [65 refs]. Semin Oncol 1999; 26: 107–114.

    CAS  PubMed  Google Scholar 

  3. Reed JC . Molecular biology of chronic lymphocytic leukemia [Review] [55 refs]. Semin Oncol 1998; 25: 11–18.

    CAS  PubMed  Google Scholar 

  4. Kay NE, Bone ND, Tschumper RC, Howell KH, Geyer SM, Dewald GW et al. B-CLL cells are capable of synthesis and secretion of both pro- and anti-angiogenic molecules. Leukemia 2002; 16: 911–919.

    Article  CAS  PubMed  Google Scholar 

  5. Ferrara N, Davis-Smyth T . The biology of vascular endothelial growth factor. Endocr Rev 1997; 18: 4–25.

    Article  CAS  PubMed  Google Scholar 

  6. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380: 439–442.

    Article  CAS  PubMed  Google Scholar 

  7. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z . Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13: 9–22.

    Article  CAS  PubMed  Google Scholar 

  8. Ortega N, Hutchings H, Plouet J . Signal relays in the VEGF system [Review] [130 refs]. Frontiers Biosci 1999; 4: D141–D152.

    CAS  Google Scholar 

  9. Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 1994; 8: 1897–1909.

    Article  CAS  PubMed  Google Scholar 

  10. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 1998; 282: 946–949.

    Article  CAS  PubMed  Google Scholar 

  11. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62–66.

    Article  CAS  PubMed  Google Scholar 

  12. Fong GH, Rossant J, Gertsenstein M, Breitman ML . Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376: 66–70.

    Article  CAS  PubMed  Google Scholar 

  13. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995; 376: 70–74.

    Article  CAS  PubMed  Google Scholar 

  14. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380: 435–439.

    Article  CAS  PubMed  Google Scholar 

  15. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis [see comment]. Cell 1996; 87: 1171–1180.

    Article  CAS  PubMed  Google Scholar 

  16. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis [see comment]. Science 1997; 277: 55–60.

    Article  CAS  PubMed  Google Scholar 

  17. Hanahan D . Signaling vascular morphogenesis and maintenance [comment]. Science 1997; 277: 48–50.

    Article  CAS  PubMed  Google Scholar 

  18. de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT . The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992; 255: 989–991.

    Article  CAS  PubMed  Google Scholar 

  19. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M . A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor (VEGF). Oncogene 1995; 10: 135–147.

    CAS  PubMed  Google Scholar 

  20. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992; 187: 1579–1586.

    Article  CAS  PubMed  Google Scholar 

  21. Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB . Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 1991; 6: 1677–1683.

    CAS  PubMed  Google Scholar 

  22. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin C . Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994; 269: 26988–26995.

    CAS  PubMed  Google Scholar 

  23. Landgren E, Schiller P, Cao Y, Claesson-Welsh L . Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1. Oncogene 1998; 16: 359–367.

    Article  CAS  PubMed  Google Scholar 

  24. Vaisman N, Gospodarowicz D, Neufeld G . Characterization of the receptors for vascular endothelial growth factor. J Biol Chem 1990; 265: 19461–19466.

    CAS  PubMed  Google Scholar 

  25. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell 1997; 89: 981–990.

    Article  CAS  PubMed  Google Scholar 

  26. Lee YK, Bone ND, Strege AK, Jelinek DF, Kay NE . VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG) in B-cell chronic lymphocytic leukemia. Blood 2004; 104: 788–794.

    Article  CAS  PubMed  Google Scholar 

  27. Rousseau S, Houle F, Landry J, Huot J . p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 1997; 15: 2169–2177.

    Article  CAS  PubMed  Google Scholar 

  28. Bartoli M, Gu X, Tsai NT, Venema RC, Brooks SE, Marrero MB et al. Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. J Biol Chem 2000; 275: 33189–33192.

    Article  CAS  PubMed  Google Scholar 

  29. Darnell Jr JE, Kerr IM, Stark GR . Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins [Review] [97 refs]. Science 1994; 264: 1415–1421.

    Article  CAS  PubMed  Google Scholar 

  30. Darnell Jr JE . STATs and gene regulation [Review] [99 refs]. Science 1997; 277: 1630–1635.

    Article  CAS  PubMed  Google Scholar 

  31. Ihle JN . STATs: signal transducers and activators of transcription [Review] [20 refs]. Cell 1996; 84: 331–334.

    Article  CAS  PubMed  Google Scholar 

  32. Bowman T, Garcia R, Turkson J, Jove R . STATs in oncogenesis [Review] [176 refs]. Oncogene 2000; 19: 2474–2488.

    Article  CAS  PubMed  Google Scholar 

  33. Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 1999; 18: 4657–4668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 1999; 10: 39–49.

    Article  CAS  PubMed  Google Scholar 

  35. Lin TS, Mahajan S, Frank DA . STAT signaling in the pathogenesis and treatment of leukemias [Review] [52 refs]. Oncogene 2000; 19: 2496–2504.

    Article  CAS  PubMed  Google Scholar 

  36. Frank DA, Mahajan S, Ritz J . Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 1999; 5: 444–447.

    Article  CAS  PubMed  Google Scholar 

  37. Frank DA, Mahajan S, Ritz J . B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J Clin Invest 1997; 100: 3140–3148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  39. Wang YZ, Wharton W, Garcia R, Kraker A, Jove R, Pledger WJ . Activation of Stat3 preassembled with platelet-derived growth factor beta receptors requires Src kinase activity. Oncogene 2000; 19: 2075–2085.

    Article  CAS  PubMed  Google Scholar 

  40. Shen Y, Schlessinger K, Zhu X, Meffre E, Quimby F, Levy DE et al. Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol 2004; 24: 407–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stoiber D, Kovarik P, Cohney S, Johnston JA, Steinlein P, Decker T . Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. J Immunol 1999; 163: 2640–2647.

    CAS  PubMed  Google Scholar 

  42. Schindler C, Shuai K, Prezioso VR, Darnell Jr JE . Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor [see comment]. Science 1992; 257: 809–813.

    Article  CAS  PubMed  Google Scholar 

  43. Liu H, Ma Y, Cole SM, Zander C, Chen K-H, Karras J et al. Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival. Blood 2003; 102: 344–352.

    Article  CAS  PubMed  Google Scholar 

  44. Fu XY, Zhang JJ . Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter. Cell 1993; 74: 1135–1145.

    Article  CAS  PubMed  Google Scholar 

  45. Bild AH, Turkson J, Jove R . Cytoplasmic transport of Stat3 by receptor-mediated endocytosis. EMBO J 2002; 21: 3255–3263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Higdon JV, Frei B . Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions [Review] [300 refs]. Crit Rev Food Sci Nutr 2003; 43: 89–143.

    Article  CAS  PubMed  Google Scholar 

  47. Sohal J, Phan VT, Chan PV, Davis EM, Patel B, Kelly LM et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood 2003; 101: 3188–3197.

    Article  CAS  PubMed  Google Scholar 

  48. Levy DE, Darnell Jr JE . Stats: transcriptional control and biological impact [Review] [161 refs]. Nat Rev Mol Cell Biol 2002; 3: 651–662.

    Article  CAS  PubMed  Google Scholar 

  49. Wen Z, Zhong Z, Darnell Jr JE . Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995; 82: 241–250.

    Article  CAS  PubMed  Google Scholar 

  50. Kovarik P, Stoiber D, Novy M, Decker T . Stat1 combines signals derived from IFN-gamma and LPS receptors during macrophage activation. EMBO J 1998; 17: 3660–3668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kovarik P, Stoiber D, Eyers PA, Menghini R, Neininger A, Gaestel M et al. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci USA 1999; 96: 13956–13961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Goh KC, Haque SJ, Williams BR . p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. EMBO J 1999; 18: 5601–5608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yamamoto H, Crow M, Cheng L, Lakatta E, Kinsella J . PDGF receptor-to-nucleus signaling of p91 (STAT1 alpha) transcription factor in rat smooth muscle cells. Exp Cell Res 1996; 222: 125–130.

    Article  CAS  PubMed  Google Scholar 

  54. Santos SC, Dias S . Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood 2004; 103: 3883–3889 [E-pub 2004 Jan 3815].

    Article  CAS  PubMed  Google Scholar 

  55. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L . VEGF-receptor signal transduction [Review] [80 refs]. Trends Biochem Sci 2003; 28: 488–494.

    Article  CAS  PubMed  Google Scholar 

  56. Jelinek DF, Tschumper RC, Stolovitzky GA, Iturria SJ, Tu Y, Lepre J et al. Identification of a global gene expression signature of B-chronic lymphocytic leukemia. Mol Cancer Res 2003; 1: 346–361.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH/NCI Grant R01 CA95241 and philanthropic support from Mr Edson Spencer.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Y K Lee, T D Shanafelt, N D Bone, A K Strege & N E Kay

  2. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    D F Jelinek

Authors
  1. Y K Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T D Shanafelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N D Bone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A K Strege
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D F Jelinek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N E Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N E Kay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, Y., Shanafelt, T., Bone, N. et al. VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance. Leukemia 19, 513–523 (2005). https://doi.org/10.1038/sj.leu.2403667

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403667

Keywords

This article is cited by

Search

Advanced search

Quick links