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
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.
|Keywords||Acute Disease, Arachidonic Acids/pharmacology, Bucladesine/pharmacology, Cell Differentiation/drug effects, Cell Movement/drug effects, Cyclic AMP/metabolism, Cyclohexanols/pharmacology, Down-Regulation/physiology, Endocannabinoids/pharmacology, Glycerides/pharmacology, Hematopoietic Stem Cells/cytology/physiology, Humans, Immunosuppressive Agents/pharmacology, Leukemia, Myeloid/*physiopathology, Ligands, MAP Kinase Signaling System/drug effects/physiology, Mutagenesis, Site-Directed, Neutrophils/*cytology, Pertussis Toxin/pharmacology, Receptor, Cannabinoid, CB2/*genetics/*metabolism, Receptors, Granulocyte Colony-Stimulating Factor/metabolism, Research Support, Non-U.S. Gov't|
Alberich Jorda, M., Rayman, N., Tas, M., Verbakel, S.E., Battista, N., van Lom, K., … Delwel, H.R.. (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. Blood. Retrieved from http://hdl.handle.net/1765/8184