Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy.

BACKGROUND Imatinib could reverse marrow angiogenesis and decrease the plasma level of vascular endothelial growth factor (VEGF) in chronic myeloid leukemia (CML) patients. Methods, materials and patients: The current study investigated the impact of four vascular endothelial growth factor type A (VEGFA) and three vascular endothelial growth factor receptor type 2 (VEGFR2) gene polymorphisms on the outcomes of 228 CML patients following imatinib therapy. VEGFA genotypes such as -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) loci and VEGFR2 genotypes (rs1531289, rs1870377 and rs2305948) were analyzed using matrix-assisted laser desorption/ionization time-of-flight-based method. RESULTS In single marker analyses, strong correlations were noted between complete cytogenetic response (CCyR) and VEGFR2 genotypes (rs1531289/rs1870377), between treatment failure and VEGFR2 genotype (rs1870377) and between progression to advanced disease and VEGFA genotypes (rs699947/rs833061). Three haplotypes of VEGFR2 gene were generated as follows: GT (46.1%), AT (27.9%) and GA (25.7%). Haplotype analyses showed good correlations between VEGFR2 haplotype and CCyR and treatment failure to imatinib. Multivariate analyses confirmed strong correlations of VEGFR2 polymorphisms (especially rs1531289, rs1870377 or VEGFR2 haplotype) with CCyR, treatment failure and of VEGFA genotype (rs699947) with progression to advanced disease. CONCLUSION The VEGFR2 gene polymorphism correlates with cytogenetic response, treatment failure following imatinib therapy for CML, while VEGFA genotype correlates with progression to advanced disease.

[1]  Y. Do,et al.  Vascular endothelial growth factor (VEGF) gene (VEGFA) polymorphism can predict the prognosis in acute myeloid leukaemia patients , 2007, British journal of haematology.

[2]  H. Wakelee,et al.  Role of Anti-angiogenesis Agents in Treating NSCLC: Focus on Bevacizumab and VEGFR Tyrosine Kinase Inhibitors , 2007, Current treatment options in oncology.

[3]  H. Kantarjian,et al.  New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance , 2006, Annals of Internal Medicine.

[4]  L. Douglass,et al.  expression and , 2006 .

[5]  E. Shin,et al.  Association between genetic variations of vascular endothelial growth factor receptor 2 and atopy in the Korean population. , 2006, The Journal of allergy and clinical immunology.

[6]  M. Shibuya.  Vascular endothelial growth factor (VEGF)-Receptor2: its biological functions, major signaling pathway, and specific ligand VEGF-E. , 2006, Endothelium : journal of endothelial cell research.

[7]  Q. Han,et al.  Identification of human chronic myelogenous leukemia progenitor cells with hemangioblastic characteristics. , 2005, Blood.

[8]  Z. Han,et al.  Elevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia , 2005, Leukemia & lymphoma.

[9]  C. Culy.  Bevacizumab: antiangiogenic cancer therapy. , 2005, Drugs of today.

[10]  E. Maltezos,et al.  VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. , 2004, Lung cancer.

[11]  D. Hicklin,et al.  Inhibition of Both the Autocrine and the Paracrine Growth of Human Leukemia with a Fully Human Antibody Directed Against Vascular Endothelial Growth Factor Receptor 2 , 2004, Leukemia & lymphoma.

[12]  G. Pagès,et al.  Imatinib mesylate (STI571) decreases the vascular endothelial growth factor plasma concentration in patients with chronic myeloid leukemia. , 2004, Blood.

[13]  M. Griesshammer,et al.  Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy. , 2004, Blood.

[14]  B. Schneeweiss,et al.  Immunohistochemical detection of VEGF in the bone marrow of patients with chronic myeloid leukemia and correlation with the phase of disease. , 2004, American journal of clinical pathology.

[15]  D. Driscoll.  Polycystic Ovary Syndrome in Adolescence , 2003, Seminars in reproductive medicine.

[16]  Susan Branford,et al.  Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. , 2003, The New England journal of medicine.

[17]  H. Kantarjian,et al.  Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia. , 2003, Leukemia research.

[18]  Ø. Bruserud,et al.  Effects of angiogenic regulators on in vitro proliferation and cytokine secretion by native human acute myelogenous leukemia blasts , 2003, European journal of haematology.

[19]  S. Rafii,et al.  Angiogenic Factors Reconstitute Hematopoiesis by Recruiting Stem Cells from Bone Marrow Microenvironment , 2003, Annals of the New York Academy of Sciences.

[20]  D. Ray,et al.  Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. , 2003, Cancer research.

[21]  K. Stamatopoulos,et al.  Clinicopathologic correlations of bone marrow angiogenesis in chronic myeloid leukemia: a morphometric study , 2003, Leukemia.

[22]  J. Melo,et al.  Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. , 2002, Molecular cancer research : MCR.

[23]  Christian Sillaber,et al.  BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. , 2002, Blood.

[24]  H. Serve,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 , 2002, Leukemia.

[25]  H. Kantarjian,et al.  Prognostic significance of cellular vascular endothelial growth factor expression in chronic phase chronic myeloid leukemia. , 2002, Blood.

[26]  M. Ratajczak,et al.  Bcr-abl-positive cells secrete angiogenic factors including matrix metalloproteinases and stimulate angiogenesis in vivo in Matrigel implants , 2002, Leukemia.

[27]  B. Druker,et al.  Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy , 2002, Leukemia.

[28]  S. Rafii,et al.  Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  S. Rafii,et al.  Vascular Endothelial Growth Factor and Angiopoietin-1 Stimulate Postnatal Hematopoiesis by Recruitment of Vasculogenic and Hematopoietic Stem Cells , 2001, The Journal of experimental medicine.

[30]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[31]  T. Grogan,et al.  Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. , 2001, Blood.

[32]  J. Melo,et al.  The molecular biology of chronic myeloid leukemia. , 2000, Blood.

[33]  W. Renner,et al.  A Common 936 C/T Mutation in the Gene for Vascular Endothelial Growth Factor Is Associated with Vascular Endothelial Growth Factor Plasma Levels , 2000, Journal of Vascular Research.

[34]  E. Estey,et al.  Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. , 2000, Blood.

[35]  M. Bottomley,et al.  Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. , 2000, Cytokine.

[36]  S. Dirnhofer,et al.  Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells , 2000, The Lancet.

[37]  G. Rodgers,et al.  Evidence of increased angiogenesis in patients with acute myeloid leukemia. , 2000, Blood.

[38]  V. Pravica,et al.  Novel polymorphisms in the promoter and 5' UTR regions of the human vascular endothelial growth factor gene. , 1999, Human immunology.

[39]  C. Peschle,et al.  KDR receptor: a key marker defining hematopoietic stem cells. , 1999, Science.

[40]  T. Grogan,et al.  Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. , 1999, Cancer research.

[41]  S. Ergün,et al.  Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. , 1997, Blood.

[42]  N. Ferrara,et al.  The biology of vascular endothelial growth factor. , 1997, Endocrine reviews.

[43]  M. Klagsbrun,et al.  Vascular endothelial growth factor and its receptors. , 1996, Cytokine & growth factor reviews.

[44]  M. Rocchi,et al.  Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. , 1996, Circulation.

[45]  K. Thomas.  Vascular Endothelial Growth Factor, a Potent and Selective Angiogenic Agent (*) , 1996, The Journal of Biological Chemistry.

[46]  M Schumacher,et al.  A bootstrap resampling procedure for model building: application to the Cox regression model. , 1992, Statistics in medicine.

[47]  J. Fiddes,et al.  The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. , 1991, The Journal of biological chemistry.

[48]  J. Friedman.  'Drug holidays' in the treatment of Parkinson's disease. A brief review. , 1985, Archives of internal medicine.