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

Y. K. Lee, T. D. Shanafelt, N. D. Bone, A. K. Strege, D. F. Jelinek, Neil E. Kay

Research output: Contribution to journalArticle

109 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)513-523
Number of pages11
JournalLeukemia
Volume19
Issue number4
DOIs
StatePublished - Apr 2005

Keywords

  • CLL
  • Nucleus
  • STAT 1 and 3
  • VEGF

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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