title: 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.
abstract: Cb2, the gene encoding the peripheral cannabinoid receptor, is located in a common virus integration site and is overex-pressed 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, CP55940. Both effects depend on the activation of G(alphai) proteins and require the mitogen-induced extracellular kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. Down-regulation of cyclic adenosine monophosphate (cAMP) levels upon G(alphai) 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 G(alphai) proteins with other currently unknown motifs. This indicates a unique mechanism by which a transforming GPCR, in a ligand-dependent manner, causes 2 distinct oncogenic effects: altered migration and block of neutrophilic development.
authors.affiliation: Erasmus MC, Department of Hematology, Dr Molewaterplein 50, 3015GE Rotterdam, The Netherlands.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Alberich Jordà
authors.forename: Nazik
authors.initials: N
authors.lastname: Rayman
authors.forename: Marjolein
authors.initials: M
authors.lastname: Tas
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Verbakel
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.forename: Kirsten
authors.initials: K
authors.lastname: van Lom
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000208:Acute Disease; D001095:Arachidonic Acids / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000503:physiopathology*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000166:cytology*; D037342:Pertussis Toxin / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics* / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols; D063388:Endocannabinoids; D005989:Glycerides; D007166:Immunosuppressive Agents; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D003994:Bucladesine; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; D000242:Cyclic AMP; D037342:Pertussis Toxin