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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1238-1250. Prepublished online as a Blood First Edition Paper on April 9, 2007; DOI 10.1182/blood-2006-02-003772. This Article Full Text (PDF) Supplemental Methods All Versions of this Article: blood-2006-02-003772v1 110/4/1238    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pillozzi, S. Articles by Arcangeli, A. Search for Related Content PubMed PubMed Citation Articles by Pillozzi, S. Articles by Arcangeli, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 15, 2006 Accepted April 5, 2007 VEGFR-1 (FLT-1), 1 integrin and hERG K+ channel form a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome Serena Pillozzi, Maria Felice Brizzi, Pietro Antonio Bernabei, Benedetta Bartolozzi, Roberto Caporale, Venere Basile, Vieri Boddi, Luigi Pegoraro, Andrea Becchetti, and Annarosa Arcangeli* Department of Experimental Pathology and Oncology, University of Firenze, Firenze, Italy Department of Internal Medicine, University of Torino, Torino, Italy O.U. Hematology, Policlinico di Careggi, Firenze, Italy Department of Laboratory Medicine, A.O.U.Careggi, Firenze, Italy Department of Public Health, Firenze, Italy Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy * Corresponding author; email: annarosa.arcangeli{at}unifi.it. Leukemia cell motility and trans-endothelial migration into extramedullary sites are regulated by angiogenic factors and are considered unfavorable prognostic factors in acute leukemias. We have studied cross talk between i) the Vascular Endothelial Growth Factor-receptor 1, FLT-1, ii) the human eag-related gene 1 (hERG1) K+ channels, iii) integrin receptors, in acute myeloid leukemia (AML) cells. FLT-1, hERG1 and the 1 integrin were found to form a macromolecular signaling complex. The latter mostly recruited the hERG1B isoform of hERG1 channels, and its assembly was necessary for FLT-1 signaling activation and AML cell migration. Both effects were inhibited when hERG1 channels were specifically blocked. A FLT-1/hERG1/1 complex was also observed in primary AML blasts, obtained from a population of human patients. The co-expression of FLT-1 and hERG1 conferred a pro-migratory phenotype to AML blasts. Such a phenotype was also observed in vivo. Herg1 positive blasts were more efficient in invading the peripheral circulation and the extramedullary sites after engraftment into immunodeficient mice. Moreover, herg1 expression in leukemia patients correlated with a higher probability of relapse and shorter survival periods. We conclude that, in AML, hERG1 channels mediate the FLT-1 dependent cell migration and invasion and hence confer a greater malignancy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. B. Ganapathi, M. Kester, and K. S. Elmslie State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy Am J Physiol Cell Physiol, April 1, 2009; 296(4): C701 - C710. [Abstract] [Full Text] [PDF] N. Rahimi, T. E. Golde, and R. D. Meyer Identification of Ligand-Induced Proteolytic Cleavage and Ectodomain Shedding of VEGFR-1/FLT1 in Leukemic Cancer Cells Cancer Res., March 15, 2009; 69(6): 2607 - 2614. [Abstract] [Full Text] [PDF] E. De Lorenzo, S. Pillozzi, M. Masselli, O. Crociani, A. Becchetti, and A. Arcangeli Potassium Channels as Novel Pharmacological Targets in Acute Myeloid Leukemia Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 4034 - 4034. [Abstract] L. Guasti, O. Crociani, E. Redaelli, S. Pillozzi, S. Polvani, M. Masselli, T. Mello, A. Galli, A. Amedei, R. S. Wymore, et al. Identification of a Posttranslational Mechanism for the Regulation of hERG1 K+ Channel Expression and hERG1 Current Density in Tumor Cells Mol. Cell. Biol., August 15, 2008; 28(16): 5043 - 5060. [Abstract] [Full Text] [PDF] A. Schwab, P. Hanley, A. Fabian, and C. Stock Potassium Channels Keep Mobile Cells on the Go Physiology, August 1, 2008; 23(4): 212 - 220. [Abstract] [Full Text] [PDF] A. Becchetti and A. Arcangeli A Comment on Ion Channels as Pharmacological Targets in Oncology J. Gen. Physiol., July 28, 2008; 132(2): 313 - 314. [Full Text] [PDF] T. Papayannopoulou and D. T. 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