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Blood, 15 July 2004, Vol. 104, No. 2, pp. 526-534. Prepublished online as a Blood First Edition Paper on March 23, 2004; DOI 10.1182/blood-2003-12-4357. This Article Full Text (PDF) Erratum (v104,p1252) All Versions of this Article: 2003-12-4357v1 104/2/526    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 Alberich Jorda, M. Articles by Delwel, R. Search for Related Content PubMed PubMed Citation Articles by Alberich Jorda, M. Articles by Delwel, R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 23, 2003 Accepted March 8, 2004 The peripheral cannabinoid receptor Cb2, frequently expressed on AML blasts, either induces a neutrophilic differentiation block or confers abnormal migration properties in a ligand-dependent manner Meritxell Alberich Jorda, Nazik Rayman, Marjolein Tas, Sandra E Verbakel, Natalia Battista, Kirsten van Lom, Bob Lowenberg, Mauro Maccarrone, and Ruud Delwel* Hematology, ErasmusMC, Rotterdam, The Netherlands Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy Department of Biomedical Sciences, University of Teramo, Teramo, Italy; Mondino-Tor Vergata- Santa Lucia Center for Experimental Neurobiology, IRCCS C. Mondino, Rome, Italy * Corresponding author; email: h.delwel{at}erasmusmc.nl. Cb2, the gene encoding the peripheral cannabinoid receptor, is located in a common virus integration site and is overexpressed in retrovirally-induced murine myeloid leukemias. Here we show that this G protein-coupled receptor (GPCR) is also aberrantly expressed in a high percentage of human acute myeloid leukemias. We investigated the mechanism of transformation by Cb2 and demonstrate that aberrant expression of this receptor on hematopoietic precursor cells results in distinct effects depending on the ligand used. Cb2-expressing myeloid precursors migrate upon stimulation by the endocannabinoid 2-arachidonoylglycerol and are blocked in neutrophilic differentiation upon exposure to another ligand, CP55,940. Both effects depend on the activation of Gi proteins and require the MEK/ERK pathway. Downregulation of cAMP levels upon Gi activation is important for migration induction, but is irrelevant for the maturation arrest. Moreover, the highly conserved G protein interacting DRY-motif, present in the second intracellular loop of GPCRs, is critical for migration, but unimportant for the differentiation block. This suggests that the Cb2-mediated differentiation block requires interaction of Gi proteins with other currently unknown motifs. This indicates a unique mechanism by which a transforming GPCR, in a ligand-dependent manner, causes two distinct oncogenic effects, i.e. altered migration and block of neutrophilic development. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CB2, a paradigm for a novel class of "onco-GPCRs"? Pierre Casellas Blood 2004 104: 302-303. [Full Text] [PDF] This article has been cited by other articles: M. Bifulco, A. M. Malfitano, S. Pisanti, and C. Laezza Endocannabinoids in endocrine and related tumours Endocr. Relat. Cancer, June 1, 2008; 15(2): 391 - 408. [Abstract] [Full Text] [PDF] J. Palazuelos, N. Davoust, B. Julien, E. Hatterer, T. Aguado, R. Mechoulam, C. Benito, J. Romero, A. Silva, M. Guzman, et al. The CB2 Cannabinoid Receptor Controls Myeloid Progenitor Trafficking: INVOLVEMENT IN THE PATHOGENESIS OF AN ANIMAL MODEL OF MULTIPLE SCLEROSIS J. Biol. Chem., May 9, 2008; 283(19): 13320 - 13329. [Abstract] [Full Text] [PDF] D. McHugh, C. Tanner, R. Mechoulam, R. G. Pertwee, and R. A. Ross Inhibition of Human Neutrophil Chemotaxis by Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct from CB1 and CB2 Mol. Pharmacol., February 1, 2008; 73(2): 441 - 450. [Abstract] [Full Text] [PDF] F. He, Z.-H. Qiao, J. Cai, W. Pierce, D.-C. He, and Z.-H. Song Involvement of the 90-kDa Heat Shock Protein (Hsp-90) in CB2 Cannabinoid Receptor-Mediated Cell Migration: A New Role of Hsp-90 in Migration Signaling of a G Protein-Coupled Receptor Mol. Pharmacol., November 1, 2007; 72(5): 1289 - 1300. [Abstract] [Full Text] [PDF] J. Palazuelos, T. Aguado, A. Egia, R. Mechoulam, M. Guzman, and I. Galve-Roperh Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation FASEB J, November 1, 2006; 20(13): 2405 - 2407. [Abstract] [Full Text] [PDF] R. Kurihara, Y. Tohyama, S. Matsusaka, H. Naruse, E. Kinoshita, T. Tsujioka, Y. Katsumata, and H. Yamamura Effects of Peripheral Cannabinoid Receptor Ligands on Motility and Polarization in Neutrophil-like HL60 Cells and Human Neutrophils J. Biol. Chem., May 5, 2006; 281(18): 12908 - 12918. [Abstract] [Full Text] [PDF] J. L. Shoemaker, M. B. Ruckle, P. R. Mayeux, and P. L. Prather Agonist-Directed Trafficking of Response by Endocannabinoids Acting at CB2 Receptors J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 828 - 838. [Abstract] [Full Text] [PDF] Q. Zhao, Z. He, N. Chen, Y.-Y. Cho, F. Zhu, C. Lu, W.-y. Ma, A. M. Bode, and Z. Dong 2-Arachidonoylglycerol Stimulates Activator Protein-1-dependent Transcriptional Activity and Enhances Epidermal Growth Factor-induced Cell Transformation in JB6 P+ Cells J. Biol. Chem., July 22, 2005; 280(29): 26735 - 26742. [Abstract] [Full Text] [PDF]

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