Identification, characterization, and function of a novel oncogene: the peripheral cannabinoid receptor Cb2.
By means of retroviral insertional mutagenesis, we identified a novel common virus integration site (cVIS) (Evi11) in murine leukemias, and demonstrated that Cb2, encoding the peripheral cannabinoid receptor, is the potential proto-oncogene located in that region. Cb2 is a 7-transmembrane G protein-coupled receptor (GPCR), which is normally expressed on B lymphocytes. Using transwell assays we observed strong migration of Cb2-expressing cells upon stimulation with 2-arachidonoylglycerol (2-AG), a potent endocannabinoid. Overexpression of Cb2 receptor on murine myeloid precursor cells causes a block of neutrophilic differentiation, a major characteristic of myeloid leukemia. Intriguingly, we could not detect functional Cb2 receptors on normal murine bone marrow precursor cells. Furthermore, analysis of human acute myeloid leukemia (AML) samples revealed the presence of CB2 mRNA transcripts in several cases. Furthermore, migration could be induced by 2-AG when analyzed in one of the patient samples. Our data suggest that the initially identified cVIS, Evi11, encodes for a murine onco-protein and that human CB2 may be involved in certain cases of human AML as well.
Jorda
Meritxell Alberich
MA
Department of Hematology, Erasmus Medical Center, the Netherlands.
Rayman
Nazik
N
Valk
Peter
P
De Wee
Eva
E
Delwel
Ruud
R
D000818:Animals; D001095:Arachidonic Acids; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C094503:glyceryl 2-arachidonate